bluuebunny/crossref_metadata_2025 huggingface dataset:
Genomic profiling ofNitrospiraspecies reveals ecological success of comammoxNitrospira
Authors: Palomo Alejandro , Dechesne Arnaud , Smets Barth F.
Published: April 2019

Nitrification was long thought to consist in the stepwise oxidation of ammonia to nitrite and of nitrite to nitrate by ammonia oxidizing and nitrite oxidizing microorganisms, respectively. Recently, single microorganisms capable of complete ammonia to nitrate oxidation (comammox) were identified in theNitrospiragenus. This genus, previously considered to only contain canonical nitrite oxidizers is diverse and has a broad environmental distribution. Yet, a global insight into the abundance, niche preference, and genomic diversity ofNitrospirais missing. Here, we established the largestNitrospiragenome database to date, revealing 68 putative species, most without cultivated representatives. We performed a global survey through read recruitment of metagenomic data from various environments against this database that identified that environmental filtering structures species distribution, without large scale biogeographical signal. The ecological success of comammoxNitrospirais evident as they outnumber and are more diverse than canonicalNitrospirain communities from all environments but wastewater treatment plants. We detect a phylogenetic signal inNitrospiraspecies habitat preference, that is strongest for canonicalNitrospiraspecies. ComammoxNitrospiraeco-evolutionary history is more complex with subclades achieving rapid niche divergence via horizontal transfer of genes, including that encoding the hydroxylamine oxidoreductase, one of the key enzymes involved in nitrification.
A chromatogram-simplified Streptomyces albus host for heterologous production of natural products
Authors: Fazal Asif , Thankachan Divya , Harris Ellie , Seipke Ryan F.
Published: April 2019

Cloning natural product biosynthetic gene clusters from cultured or uncultured sources and their subsequent expression by genetically tractable heterologous hosts is an essential strategy for the elucidation and characterisation of novel microbial natural products. The availability of suitable expression hosts is a critical aspect of this workflow. In this work, we mutagenised five endogenous biosynthetic gene clusters from Streptomyces albus S4, which reduced the complexity of chemical extracts generated from the strain and eliminated antifungal and antibacterial bioactivity. We showed that the resulting quintuple mutant can express foreign BGCs by heterologously producing actinorhodin, cinnamycin and prunustatin. We envisage that our strain will be a useful addition to the growing suite of heterologous expression hosts available for exploring microbial secondary metabolism.
Pharmacological manipulations of judgement bias: a systematic review and meta-analysis
Authors: Neville Vikki , Nakagawa Shinichi , Zidar Josefina , Paul Elizabeth S. , Lagisz Malgorzata , Bateson Melissa , Løvlie Hanne , Mendl Michael
Published: April 2019

Validated measures of animal affect are crucial to research spanning a number of disciplines including neuroscience, psychopharmacology, and animal welfare science. Judgement bias, which assesses decision-making under ambiguity, is a promising measure of animal affect. One way of validating this measure is to induce affective states using pharmacological manipulations and determine whether the predicted judgement biases are observed. Here, we conducted a systematic review and meta-analysis using data from 19 published research articles that use this approach from which 440 effect sizes were extracted. The results of the meta-analysis suggest that pharmacological manipulations overall altered judgement bias as predicted. However, there were several moderating factors including the neurobiological target of the drug, whether the drug was hypothesised to induce a relatively positive or negative affective state, dosage, and the presented cue. This may partially reflect interference from adverse effects of the drug, such as sedation. Thus, while judgement bias can be used to measure pharmacologically-induced affective states, potential adverse effects of the drug should be considered when interpreting results.
Endogenous RNAi pathway evolutionarily shapes the destiny of the antisense lncRNAs transcriptome
Authors: Szachnowski Ugo , Andus Sara , Foretek Dominika , Morillon Antonin , Wery Maxime
Published: April 2019

Antisense (as)lncRNAs are extensively degraded by the nuclear exosome and the cytoplasmic exoribonuclease Xrn1 in the budding yeast Saccharomyces cerevisiae, lacking RNA interference (RNAi). Whether the ribonuclease III Dicer affects aslncRNAs in close RNAi-capable relatives remains unknown. Using genome-wide RNA profiling, here we show that aslncRNAs are primarily targeted by the exosome and Xrn1 in the RNAi-capable budding yeast Naumovozyma castellii, Dicer only affecting Xrn1-sensitive lncRNAs (XUTs) levels in Xrn1-deficient cells. The dcr1 and xrn1 mutants display synergic growth defects, indicating that Dicer becomes critical in the absence of Xrn1. Small RNA sequencing showed that Dicer processes aslncRNAs into small RNAs, with a preference for asXUTs. Consistently, Dicer localizes into the cytoplasm. Finally, we observed an expansion of the exosome-sensitive antisense transcriptome in N. castellii compared to S. cerevisiae, suggesting that the presence of cytoplasmic RNAi has reinforced the nuclear RNA surveillance machinery to temper aslncRNAs expression. Our data provide fundamental insights into aslncRNAs metabolism and open perspectives into the possible evolutionary contribution of RNAi in shaping the aslncRNAs transcriptome.
Telomeric small RNAs in the genus Caenorhabditis
Authors: Frenk Stephen , Lister-Shimauchi Evan H. , Ahmed Shawn
Published: April 2019

Telomeric DNA is composed of simple tandem repeat sequences and has a G-rich strand that runs 5’ to 3’ towards the chromosome terminus. Small RNAs with homology to telomeres have been observed in several organisms and could originate from telomeres or from interstitial telomere sequences (ITSs), which are composites of degenerate and perfect telomere repeat sequences found on chromosome arms. We identified C. elegans small RNAs composed of the Caenorhabditis telomere sequence (TTAGGC)n with up to three mismatches, which might interact with telomeres. We rigorously defined ITSs for genomes of C. elegans and for two closely related nematodes, C. briggsae and C. remanei. We found that most telomeric small RNAs with mismatches originated from ITSs, which were depleted from mRNAs and but were enriched in introns whose genes often displayed hallmarks of genomic silencing. C. elegans small RNAs composed of perfect telomere repeats were very rare but were increased by several orders of magnitude in C. briggsae and C. remanei. Major small RNA species in C. elegans begin with a 5’ guanine nucleotide, which was strongly depleted from perfect telomeric small RNAs of all three Caenorhabditis species. Perfect telomeric small RNAs corresponding to the G-rich strand of the telomere commonly began with 5’ UAGGCU and 5’UUAGGC, whereas C-rich strand RNAs commonly begin with 5’CUAAGC. In contrast, telomeric small RNAs with mismatches had a mixture of all four 5’ nucleotides. Together, our results imply that perfect telomeric small RNAs have a mechanism of biogenesis that is distinct from known classes of small RNAs and that a dramatic change in their regulation occurred during recent Caenorhabditis evolution.
Exploring and analysing immune single cell multi-omics data with VDJView
Authors: Samir Jerome , Rizzetto Simone , Gupta Money , Luciani Fabio
Published: April 2019

Background

Single cell RNA sequencing provides unprecedented opportunity to simultaneously explore the transcriptomic and immune receptor diversity of T and B cells. However, there are limited tools available that simultaneously analyse large multi-omics datasets integrated with metadata such as patient and clinical information.

Results

We developed VDJView, which permits the simultaneous or independent analysis and visualisation of gene expression, immune receptors, and clinical metadata of both T and B cells. This tool is implemented as an easy-to-use R shiny web-application, which integrates numerous gene expression and TCR analysis tools, and accepts data from plate-based sorted or high-throughput single cell platforms. We utilised VDJView to analyse several 10X scRNA-seq datasets, including a recent dataset of 150,000 CD8+ T cells with available gene expression, TCR sequences, quantification of 15 surface proteins, and 44 antigen specificities (across viruses, cancer, and self-antigens). We performed quality control, filtering of tetramer non-specific cells, clustering, random sampling and hypothesis testing to discover antigen specific gene signatures which were associated with immune cell differentiation states and clonal expansion across the pathogen specific T cells. We also analysed 563 single cells (plate-based sorted) obtained from 11 subjects, revealing clonally expanded T and B cells across primary cancer tissues and metastatic lymph-node. These immune cells clustered with distinct gene signatures according to the breast cancer molecular subtype. VDJView has been tested in lab meetings and peer-to-peer discussions, showing effective data generation and discussion without the need to consult bioinformaticians.

Conclusions

VDJView enables researchers without profound bioinformatics skills to analyse immune scRNA-seq data, integrating and visualising this with clonality and metadata profiles, thus accelerating the process of hypothesis testing, data interpretation and discovery of cellular heterogeneity. VDJView is freely available at https://bitbucket.org/kirbyvisp/vdjview.
Retrospective serological analysis reveals presence of the emerging lagovirus RHDV2 in Australian wild rabbits at least six months prior to its first detection
Authors: Strive Tanja , Piper Melissa , Huang Nina , Mourant Roslyn , Kovaliski John , Capucci Lorenzo , Cox Tarnya E , Smith Ina
Published: April 2019

The lagovirus Rabbit Haemorrhagic Disease Virus (RHDV) has been circulating in Australia since the mid-1990s when it was deliberately released to control overabundant rabbit populations. In recent years, the viral diversity of different RHDVs in Australia has increased, and currently four different types of RHDV are known to be circulating. To allow for ongoing epidemiological studies and impact assessments of these viruses on Australian wild rabbit populations, it is essential that serological tools are updated. To this end, Reference sera were produced against all four virulent RHDVs (including RHDV2) known to be present in Australia and tested in a series of available immunological assays originally developed for the prototype RHDV, to assess patterns of cross reactivity and the usefulness of these assays to detect lagovirus antibodies, either in a generic or specific manner. Enzyme Linked Immuno Sorbent Assays (ELISAs) developed to detect antibody isotypes IgM, IgA and IgG were sufficiently cross reactive to detect antibodies raised against all four virulent lagoviruses. For the more specific detection of antibodies to the antigenically more different RHDV2, a competition ELISA was adapted using RHDV2 specific monoclonal antibodies in combination with Australian viral antigen. Archival serum banks from a long term rabbit monitoring site where rabbits were sampled quarterly over a period of six years were re-screened using this assay, and revealed serological evidence for the arrival of RHDV2 in this population at least six months prior to its initial detection in Australia in a deceased rabbit in May 2015. The serological methods and reference reagents described here will provide valuable tools to study presence, prevalence and impact of RHDV2 on Australian rabbit populations; however the discrimination of different antigenic variants of RHDVs as well as mixed infections at the serological level remains challenging.
Vinculin anchors contractile actin to the cardiomyocyte adherens junction
Authors: Merkel Chelsea D. , Li Yang , Raza Qanber , Stolz Donna B. , Kwiatkowski Adam V.
Published: April 2019

The adherens junction (AJ) couples the actin cytoskeletons of neighboring cells to allow mechanical integration and tissue organization. The physiological demands of intercellular adhesion require that the AJ be responsive to dynamic changes in force while maintaining mechanical load. These demands are tested in the heart, where cardiomyocyte AJs must withstand repeated cycles of actomyosin-mediated contractile force. Here we show that force-responsive cardiomyocyte AJs recruit actin-binding ligands to selectively couple actin networks and promote contact maturation. We employed a panel of N-cadherin-αE-catenin fusion proteins to rebuild AJs with specific actin linkages in N-cadherin-null cardiomyocytes. In this system, vinculin recruitment was required to rescue myofibril integration and desmosome assembly at nascent contacts. In contrast, loss of vinculin disrupted junction morphology and blocked myofibril integration. Our results identify vinculin as a critical link to contractile actomyosin and offer insight to how actin integration at the AJ is regulated to provide mechanical stability and cellular organization.
Direct observation of branching MT nucleation in living animal cells
Authors: Verma Vikash , Maresca Thomas J.
Published: April 2019

Centrosome-mediated microtubule (MT) nucleation has been well-characterized; however, numerous non-centrosomal MT nucleation mechanisms exist. The branching MT nucleation pathway envisages that the γ-tubulin ring complex (γ-TuRC) is recruited to MTs by the augmin complex to initiate nucleation of new MTs. While the pathway is well-conserved at a molecular and functional level, branching MT nucleation by core constituents has never been directly observed in animal cells. Here, multi-color TIRF microscopy was applied to visualize and quantitatively define the entire process of branching MT nucleation in dividingDrosophilacells. The stereotypical branching nucleation event entailed augmin first binding to a “mother” MT, recruitment of γ-TuRC after 16s, followed by nucleation 15s later of a “daughter” MT at a 36° branch angle. Daughters typically remained attached throughout their ~40s lifetime unless the mother depolymerized past the branch point. Assembly of branched MT arrays, which did not require D-TPX2 (Drosophila TPX2) or evident regulation by a RanGTP gradient, enhanced localized RhoA activation during cytokinesis.
Biologically plausible learning in a deep recurrent spiking network
Authors: Rotermund David , Pawelzik Klaus R.
Published: April 2019

Artificial deep convolutional networks (DCNs) meanwhile beat even human performance in challenging tasks. Recently DCNs were shown to also predict real neuronal responses. Their relevance for understanding the neuronal networks in the brain, however, remains questionable. In contrast to the unidirectional architecture of DCNs neurons in cortex are recurrently connected and exchange signals by short pulses, the action potentials. Furthermore, learning in the brain is based on local synaptic mechanisms, in stark contrast to the global optimization methods used in technical deep networks. What is missing is a similarly powerful approach with spiking neurons that employs local synaptic learning mechanisms for optimizing global network performance. Here, we present a framework consisting of mutually coupled local circuits of spiking neurons. The dynamics of the circuits is derived from first principles to optimally encode their respective inputs. From the same global objective function a local learning rule is derived that corresponds to spike-timing dependent plasticity of the excitatory inter-circuit synapses. For deep networks built from these circuits self-organization is based on the ensemble of inputs while for supervised learning the desired outputs are applied in parallel as additional inputs to output layers.

Generality of the approach is shown with Boolean functions and its functionality is demonstrated with an image classification task, where networks of spiking neurons approach the performance of their artificial cousins. Since the local circuits operate independently and in parallel, the novel framework not only meets a fundamental property of the brain but also allows for the construction of special hardware. We expect that this will in future enable investigations of very large network architectures far beyond current DCNs, including also large scale models of cortex where areas consisting of many local circuits form a complex cyclic network.
Cohort Profile: HealthWise Wales. A research register and data collection and analysis platform with linkage to NHS datasets in Wales
Authors: Hurt Lisa , Ashfield-Watt Pauline , Townson Julia , Heslop Luke , Copeland Lauren , Atkinson Mark , Horton Jeffrey , Paranjothy Shantini
Published: April 2019

Purpose

Recruitment and follow-up in epidemiological studies is challenging, time-consuming and expensive. Combining online data collection with a register of individuals who agree to be contacted with information on research opportunities provides an efficient, cost-effective platform for population-based research. HealthWise Wales (HWW) aims to support researchers by recruiting a cohort of “research-ready” individuals; advertising relevant studies to these participants; providing access to cohort data for secondary analyses; and supporting data collection on specific topics that can be linked with healthcare data.

Participants

Adults (aged 16 and above) living or receiving their healthcare in Wales are eligible for inclusion. Participants consent to be followed-up every 6 months; for their details to be used to access their routinely-collected NHS records for research purposes; to be contacted about research projects in which they could participate; and to be informed about involvement or engagement opportunities. Data are collected using a web-based application, with new questionnaires added every six months. Data collection on socio-demographic and lifestyle factors is repeated at two-to-three year intervals. Recruitment is ongoing, with 21,779 active participants (alive and currently registered).

Findings to date

99% of participants have complete information on age and sex, and 64% have completed questionnaires on socio-demographic and lifestyle factors. These data can be linked with national health databases within the Secure Anonymised Information Linkage (SAIL) databank, with 93% of participants matching a record in SAIL. HWW has facilitated recruitment of 43,826 participants to 15 different studies.

Future plans

The medium-term goal for the project is to enrol at least 50,000 adults. Recruitment strategies are being devised to achieve a study sample that closely models the population of Wales, with sufficient numbers in socio-demographic subgroups to allow for the selection of populations for research from those groups. Potential bio-sampling methods are also currently being explored.
Meningeal Worm Infection in Central Iowa Goat Herds II: Individual Cases and Treatment Using a Camelid Therapeutic Protocol
Authors: Smith Joe , Kreuder Amanda , Breuer Ryan , Still-Brooks Kelly
Published: April 2019

Summary and Implications

Meningeal worm (Paralaphostrongylus tenuis) infection, also known as cerebrospinal nematodiasis, is a common parasitic infection in New World Camelids in the United States. There is also a considerable risk for this disease in the Boer goat population. Despite the rapidly increasing size of the national goat herd, there are no treatment protocols reported in the literature for goats with this disease. This study describes a successful clinical approach and treatment of 3 Boer goat cases with therapy previously reported for use in New World Camelids. The clinical presentation, diagnosis, and long-term outcome of P. tenuis infections in these goats presented to ISU Food Animal and Camelid Hospital (FACH) is reported here within. Practitioners should be aware that clinical presentation and diagnosis are similar for goats as reported for camelids with cerebrospinal nematodiasis. Additionally, the described treatment protocols for camelids appear to demonstrate a comparative efficacy in goats.
Status of Soil-transmitted helminthiasis among pregnant women attending antenatal clinic in Kilifi county hospital, Kenya
Authors: Njeru Albert , Mutuku Francis , Muriu Simon
Published: April 2019

Soil-transmitted helminthes (STH) refers to parasites whose life cycle depends on a period of development outside the human host typically in a moist or warm soil. The most important geohelminths are; roundworms (Ascaris lumbricoides), whipworms (Trichuris trichiura) and hookworms (Necator americanusandAncylostoma duodenale). The study aimed at investigating the current epidemiological status of soil-transmitted helminth infections among pregnant women in Kilifi County hospital (KCH) following the intervention of preventive chemotherapy.

Data collection and analysis involved evaluation of transmission trends of geohelminths from the previous surveys/ hospital records, use of direct fecal smears and Kato-Katz smears in estimation of prevalence and infection intensity and the use of structured questionnaires for the assessment of the predisposing factors associated with STH infections. Logistic regression analysis was employed to determine the risk factors associated with STH infections.

A total of 191 stool samples were collected and analyzed. Three species of soil-transmitted helminths (STHs) were identified with the overall prevalence of any STH infection being 16.75%.Trichuris trichiurawas predominant (8.38 %), followed byA. lumbricoides(7.85%) then hookworms (6.29 %). About 10.99% of the participants had a single worm infection, 5.76 % had double co-infections and none of the participants had triple infection.

Preventive chemotherapy appears to give maximal returns in terms of reducing significantly the number of geohelminths reported since 2001. The study recommended the routine stool analysis in the antenatal profile, provision of alternative sources of iron to the pregnant women in order to reduce the tendency for soil consumption and the associated risk of STH infections, provision of safe water for domestic use, improved sanitation and proper personal hygiene (WASH).
Hippocampal network reorganization underlies the formation of a temporal association memory
Authors: Ahmed Mohsin S. , Priestley James B. , Castro Angel , Stefanini Fabio , Balough Elizabeth M. , Lavoie Erin , Mazzucato Luca , Fusi Stefano , Losonczy Attila
Published: April 2019

Episodic memory requires linking events in time, a function dependent on the hippocampus. In “trace” fear conditioning, animals learn to associate a neutral cue with an aversive stimulus despite their separation in time by a delay period on the order of tens of seconds. But how this temporal association forms remains unclear. Here we use 2-photon calcium imaging to track neural population dynamics over the complete time-course of learning and show that, in contrast to previous theories, the hippocampus does not generate persistent activity to bridge the time delay. Instead, learning is concomitant with broad changes in the active neural population in CA1. While neural responses were highly stochastic in time, cue identity could be reliably read out from population activity rates over longer timescales after learning. These results question the ubiquity of neural sequences during temporal association learning, and suggest that trace fear conditioning relies on mechanisms that differ from persistent activity accounts of working memory.
Lapses in perceptual decisions reflect exploration
Authors: Pisupati Sashank , Chartarifsky-Lynn Lital , Khanal Anup , Churchland Anne K.
Published: April 2019

Perceptual decision-makers often display a constant rate of errors independent of evidence strength. These “lapses” are treated as a nuisance arising from noise tangential to the decision, e.g. inattention or motor errors. Here, we use a multisensory decision task in rats to demonstrate that these explanations cannot account for lapses’ stimulus dependence. We propose a novel explanation: lapses reflect a strategic trade-off between exploiting known rewarding actions and exploring uncertain ones. We tested the model’s predictions by selectively manipulating one action’s reward magnitude or probability. As uniquely predicted by this model, changes were restricted to lapses associated with that action. Finally, we show that lapses are a powerful tool for assigning decision-related computations to neural structures based on disruption experiments (here, posterior striatum and secondary motor cortex). These results suggest that lapses reflect an integral component of decision-making and are informative about action values in normal and disrupted brain states.
Characteristics of respiratory measures in young adults scanned at rest, including systematic changes and “missed” respiratory events
Authors: Power Jonathan D. , Silver Benjamin M. , Martin Alex , Jones Rebecca M.
Published: April 2019

Breathing rate and depth influence the concentration of carbon dioxide in the blood, altering cerebral blood flow and thus functional magnetic resonance imaging (fMRI) signals. Such respiratory fluctuations can have substantial influence in studies of fMRI signal covariance in subjects at rest, the so-called “resting state functional connectivity” technique. If respiration is monitored during fMRI scanning, it is typically done using a belt about the subject’s abdomen to record abdominal circumference. Several measures have been derived from these belt records, including the windowed envelope of the waveform (ENV), the windowed variance in the waveform (respiration variation, RV), and a measure of the amplitude of each breath divided by the cycle time of the breath (respiration volume per time, RVT). Any attempt to gauge respiratory contributions to fMRI signals requires a respiratory measure, but little is known about how these measures compare to each other, or how they perform beyond the small studies in which they were initially proposed. In this paper, we examine the properties of these measures in hundreds of healthy young adults scanned for an hour each at rest, a subset of the Human Connectome Project chosen for having high-quality physiological records. We find: 1) ENV, RV, and RVT are all similar, though ENV and RV are more similar to each other than to RVT; 2) respiratory events like deep breaths exhibit characteristic fMRI signal changes, head motions, and image quality abnormalities time-locked to deep breaths evident in the belt traces; 3) all measures can “miss” respiratory events evident in the belt traces; 4) RVT “misses” deep breaths (i.e., yawns and sighs) more than ENV or RV; 5) all respiratory measures change systematically over the course of a 14.4-minute scan, decreasing in mean value. We discuss the implication of these findings for the literature, and ways to move forward in modeling respiratory influences on fMRI scans.

Highlights

- Examines 3 respiratory measures in resting state fMRI scans of healthy young adults

- All respiratory measures “miss” respiratory events, some more than others

- Respiration volume per time (RVT) frequently “misses” deep breaths

- All respiratory measures decrease systematically over 14.4 minute scans

- Systematic decreases are due to decreased breathing depth and rate
Towards Quantitative Imaging Biomarkers of Tumor Dissemination: a Multi-scale Parametric Modeling of Multiple Myeloma
Authors: Piraud Marie , Wennmann Markus , Kintzelé Laurent , Hillengass Jens , Keller Ulrich , Langs Georg , Weber Marc-André , Menze Björn H.
Published: April 2019

The advent of medical imaging and automatic image analysis is bringing the full quantitative assessment of lesions and tumor burden at every clinical examination within reach. This opens avenues for the development and testing of functional disease models, as well as their use in the clinical practice for personalized medicine. In this paper, we introduce a Bayesian statistical framework, based on mixed-effects models, to quantitatively test and learn functional disease models at different scales, on population longitudinal data. We also derive an effective mathematical model for the crossover between initially detected lesions and tumor dissemination, based on the Iwata-Kawasaki-Shigesada model. We finally propose to leverage this descriptive disease progression model into model-aware biomarkers for personalized risk-assessment, taking all available examinations and relevant covariates into account. As a use case, we study Multiple Myeloma, a disseminated plasma cell cancer, in which proper diagnostics is essential, to differentiate frequent precursor state without end-organ damage from the rapidly developing disease requiring therapy. After learning the best biological models for local lesion growth and global tumor burden evolution on clinical data, and computing corresponding population priors, we use individual model parameters as biomarkers, and can study them systematically for correlation with external covariates, such as sex or location of the lesion. On our cohort of 63 patients with smoldering Multiple Myeloma, we show that they perform substantially better than other radiological criteria, to predict progression into symptomatic Multiple Myeloma. Our study paves the way for modeling disease progression patterns for Multiple Myeloma, but also for other metastatic and disseminated tumor growth processes, and for analyzing large longitudinal image data sets acquired in oncological imaging. It shows the unprecedented potential of model-based biomarkers for better and more personalized treatment decisions and deserves being validated on larger cohorts to establish its role in clinical decision making.
Automated analysis of large-scale NMR data generates metabolomic signatures and links them to candidate metabolites
Authors: Khalili Bita , Tomasoni Mattia , Mattei Mirjam , Parera Roger Mallol , Sonmez Reyhan , Krefl Daniel , Rueedi Rico , Bergmann Sven
Published: April 2019

Identification of metabolites in large-scale 1H NMR data from human biofluids remains challenging due to the complexity of the spectra and their sensitivity to pH and ionic concentrations. In this work, we test the capacity of three analysis tools to extract metabolite signatures from 968 NMR profiles of human urine samples. Specifically, we studied sets of co-varying features derived from Principal Component Analysis (PCA), the Iterative Signature Algorithm (ISA) and Averaged Correlation Profiles (ACP), a new method we devised inspired by the STOCSY approach. We used our previously developed metabomatching method to match the sets generated by these algorithms to NMR spectra of individual metabolites available in public databases. Based on the number and quality of the matches we concluded that both ISA and ACP can robustly identify about a dozen metabolites, half of which were shared, while PCA did not produce any signatures with robust matches.
Nerve Excitability Differences in Slow and Fast Motor Axons of the Rat: more than just Ih
Authors: Bell James M. , Lorenz Chad , Jones Kelvin E.
Published: April 2019

Objective

The objective was to determine if choice of anaesthetic confounded previous conclusions about the differences in nerve excitability indices between fast and slow motor axons.

Methodology

Nerve excitability of the rat sciatic nerve was tested while measuring responses of motor axons innervating the slow-twitch soleus (SOL) and fast-twitch tibialis anterior (TA) muscles. The experiments were conducted with sodium pentobarbital (SP) anaesthetic and compared to previous results that used ketamine-xylazine (KX).

Results and Conclusions

Previous conclusions about the differences in nerve excitability indices between TA and SOL motor axons using KX were corroborated and extended when experiments were done with SP. Nerve excitability indices sensitive to changes in hyperpolarization-activated inwardly rectifying cation current (Ih) indicated an increase in Ih in SOL axons compared to TA axons (e.g. S3 (−100 %), t=7.949 (df=10), p < 0.0001; TEh (90–100 ms), t=2.659 (df=20), p = 0.0145; hyperpolarizing I/V slope, t=4.308 (df=19), p = 0.0004). SOL axons also had a longer strength-duration time constant (t=3.35 (df=20), p = 0.0032) and a longer and larger magnitude relative refractory period (RRP (ms) t=3.53 (df=12), p = 0.0041; Refractoriness at 2 ms t=0.0055 (df=9), p = 0.0055).

Anaesthetic choice affected many measures of peripheral nerve excitability with differences most apparent in tests of threshold electrotonus and recovery cycle. For example, recovery cycle with KX lacked a clear superexcitable and late subexcitable period. We conclude that KX had a confounding effect on nerve excitability results consistent with ischaemic depolarization. Results using SP revealed the full extent of differences in nerve excitability measures between putative slow and fast motor axons of the rat. These differences have important implications for the use of nerve excitability measures during processes such as ageing where it is believed that there is a selective loss of fast axons.

New & Noteworthy

Nerve excitability testing is a tool used to provide insight into the properties of ion channels in peripheral nerves. It is used clinically to assess pathophysiology of motor axons. Researchers customarily think of motor axons as homogeneous; however, we demonstrate there are clear differences between fast and slow axons in the rat. This is important for interpreting results with selective motor neuronopathy, like aging where fast axons are at high risk of degeneration.
Reductive TCA cycle enzymes and reductive amino acid synthesis pathways contribute to electron balance in aRhodospirillum rubrumCalvin cycle mutant
Authors: McCully Alexandra L. , Onyeziri Maureen C. , LaSarre Breah , Gliessman Jennifer R. , McKinlay James B.
Published: April 2019

Purple nonsulfur bacteria (PNSB) use light for energy and organic substrates for carbon and electrons when growing photoheterotrophically. This lifestyle generates more reduced electron carriers than are required for biosynthesis, even during consumption of some of the most oxidized organic substrates like malate and fumarate. Excess reduced electron carriers must be oxidized for photoheterotrophic growth to occur. Diverse PNSB commonly rely on the CO2-fixing Calvin cycle to oxidize excess reduced electron carriers. Some PNSB also produce H2or reduce terminal electron acceptors as alternatives to the Calvin cycle.Rhodospirillum rubrumCalvin cycle mutants defy this trend by growing phototrophically on malate or fumarate without H2production or access to terminal electron acceptors. We used13C-tracer experiments to examine how aRs. rubrumCalvin cycle mutant maintains electron balance under such conditions. We detected the reversal of some TCA cycle enzymes, which carried reductive flux from malate or fumarate to α-ketoglutarate. This pathway and the reductive synthesis of amino acids derived from α-ketoglutarate are likely important for electron balance, as supplementing the growth medium with α-ketoglutarate-derived amino acids preventedRs. rubrumCalvin cycle mutant growth unless a terminal electron acceptor was provided. Flux estimates also suggested that the Calvin cycle mutant preferentially synthesized isoleucine using the reductive threonine-dependent pathway instead of the less-reductive citramalate-dependent pathway. Collectively, our results suggest that alternative biosynthetic pathways can contribute to electron balance within the constraints of a relatively constant biomass composition.
Data-driven models reveal the organization of diverse cognitive functions in the brain
Authors: Nakai Tomoya , Nishimoto Shinji
Published: April 2019

Our daily life is realized by the complex orchestrations of diverse brain functions including perception, decision, and action. One of the central issues in cognitive neuroscience is to reveal the complete representations underlying such diverse functions. Recent studies have revealed representations of natural perceptual experiences using encoding models1–5. However, there has been little attempt to build a quantitative model describing the cortical organization of multiple active, cognitive processes. Here, we measured brain activity using functional MRI while subjects performed over 100 cognitive tasks, and examined cortical representations with two voxel-wise encoding models6. A sparse task-type encoding model revealed a hierarchical organization of cognitive tasks, their representation in cognitive space, and their mapping onto the cortex. A cognitive factor encoding model utilizing continuous intermediate features by using metadata-based inferences7 predicted brain activation patterns for more than 80 % of the cerebral cortex and decoded more than 95 % of tasks, even under novel task conditions. This study demonstrates the usability of quantitative models of natural cognitive processes and provides a framework for the comprehensive cortical organization of human cognition.
Engineering acetyl-CoA metabolic shortcut for eco-friendly production of polyketides triacetic acid lactone inYarrowia lipolytica
Authors: Liu Huan , Marsafari Monireh , Wang Fang , Deng Li , Xu Peng
Published: April 2019

Acetyl-CoA is the central metabolic node connecting glycolysis, Krebs cycle and fatty acids synthase. Plant-derived polyketides, are assembled from acetyl-CoA and malonyl-CoA, represent a large family of biological compounds with diversified bioactivity. Harnessing microbial bioconversion is considered as a feasible approach to large-scale production of polyketides from renewable feedstocks. Most of the current polyketide production platform relied on the lengthy glycolytic steps to provide acetyl-CoA, which inherently suffers from complex regulation with metabolically-costly cofactor/ATP requirements. Using the simplest polyketide triacetic acid lactone (TAL) as a target molecule, we demonstrate that acetate uptake pathway in oleaginous yeast (Yarrowia lipolytica) could function as an acetyl-CoA shortcut to achieve metabolic optimality in producing polyketides. We identified the metabolic bottlenecks to rewire acetate utilization for efficient TAL production inY. lipolytica, including generation of the driving force for acetyl-CoA, malonyl-CoA and NADPH. The engineered strain, with the overexpression of endogenous acetyl-CoA carboxylase (ACC1), malic enzyme (MAE1) and a bacteria-derived cytosolic pyruvate dehydrogenase (PDH), affords robust TAL production with titer up to 4.76 g/L from industrial glacier acetic acid in shake flasks, representing 8.5-times improvement over the parental strain. The acetate-to-TAL conversion ratio (0.149 g/g) reaches 31.9% of the theoretical maximum yield. The carbon flux through this acetyl-CoA metabolic shortcut exceeds the carbon flux afforded by the native acetyl-CoA pathways. Potentially, acetic acid could be manufactured in large-quantity at low-cost from Syngas fermentation or heterogenous catalysis (methanol carbonylation). This alternative carbon sources present a metabolic advantage over glucose to unleash intrinsic pathway limitations and achieve high carbon conversion efficiency and cost-efficiency. This work also highlights that low-cost acetic acid could be sustainably upgraded to high-value polyketides by oleaginous yeast species in an eco-friendly and cost-efficient manner.
In vitro evaluation of factor IX as novel treatment for factor XI deficiency
Authors: Bakhtiari Kamran , Meijers Joost C.M.
Published: April 2019

Factor XI deficiency is associated with mild to moderate bleeding upon injury. Treatment of bleeding in patients can be a challenge due to the limited availability of factor XI concentrates that may also have thrombotic side effects, and the volume overload as a result of plasma transfusion. In our in vitro study, we established that recombinant factor IX concentrate Benefix® (Pfizer) was able to potently enhance thrombin generation in factor XI depleted plasma when coagulation was initiated via the extrinsic pathway. This was due to the contamination of Benefix® with very low amounts of factor IXa that compensated for the lack of factor XI in plasma. Our data suggest that bleeding due to factor XI deficiency or antithrombotic therapy targeting factor XI may be treated with certain factor IX concentrates, which should be investigated in future clinical studies.
Organization of Associating or Crosslinked Actin Filaments in Confinement
Authors: Koudehi Maral Adeli , Rutkowski David M. , Vavylonis Dimitrios
Published: April 2019

A key factor of actin cytoskeleton organization in cells is the interplay between the dynamical properties of actin filaments and cell geometry, which restricts, confines and directs their orientation. Crosslinking interactions among actin filaments, together with geometrical cues and regulatory proteins can give rise to contractile rings in dividing cells and actin rings in neurons. Motivated by recent in vitro experiments, in this work we performed computer simulations to study basic aspects of the interplay between confinement and attractive interactions between actin filaments. We used a spring-bead model and Brownian dynamics to simulate semiflexible actin filaments that polymerize in a confining sphere with a rate proportional to the monomer concentration. We model crosslinking, or attraction through the depletion interaction, implicitly as an attractive short-range potential between filament beads. In confining geometries smaller than the persistence length of actin filaments, we show rings can form by curving of filaments of length comparable to, or longer than the confinement diameter. Rings form for optimal ranges of attractive interactions that exist in between open bundles, irregular loops, aggregated and unbundled morphologies. The probability of ring formation is promoted by attraction to the confining sphere boundary and decreases for large radii and initial monomer concentrations, in agreement with prior experimental data. The model reproduces ring formation along the flat axis of oblate ellipsoids.
Warming increases the cost of growth in a model vertebrate
Authors: Barneche Diego R. , Jahn Miki , Seebacher Frank
Published: April 2019

Growth rates directly influence individual fitness and constrain the flow of energy within food webs. Determining what factors alter the energetic cost of growth is therefore fundamental to ecological and evolutionary models.

Here, we used theory to derive predictions about how the cost of growth varies over ontogeny and with temperature. We tested these predictions by measuring resting oxygen consumption and growth rates of zebrafish (Danio rerio) at four temperature treatments (20°C, 26°C, 29°C, 32°C). We calibrated oxygen consumption for ATP production by measuring the efficiency of mitochondria (P/O ratios) at the end of the experiment.

We show that, when compared to growth rates, rates of resting oxygen consumption exhibited a significantly higher temperature dependence and significantly lower mass scaling. P/O ratios varied substantially among individuals, but did not account for the observed difference in temperature dependence between rates. Consequently, the cost of growth was significantly higher at earlier ontogenetic stages, and it increased twofold between 20°C and 32°C. Temperature systematically decreased the size of adults between 26°C and 32°C.

To the best of our knowledge, our study represents the first attempt to characterise how the cost of growth varies over ontogeny and across temperatures in a model vertebrate. Rising temperatures will substantially alter the structure of ecosystems and the distribution of biomass in food webs because they drive a decline in the average size of individuals, and because higher costs of growth lead to inefficient energy transfer between trophic levels.

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Grassland biodiversity restoration increases resistance of carbon fluxes to drought
Authors: Cole Andrew J. , Griffiths Robert I. , Ward Susan E. , Whitaker Jeanette , Ostle Nicholas J. , Bardgett Richard D.
Published: April 2019

Evidence suggests that the restoration of plant diversity in grasslands not only brings benefits for biodiversity conservation, but also the delivery of ecosystem services. While biodiversity‐function experiments show that greater plant diversity increases resistance of plant productivity to climate extremes, it is not known whether real‐world management options for grassland restoration likewise stabilize ecosystem responses to extreme climate events.

We used a long‐term (23 year) field experiment in northern England to test the hypothesis that management aimed at biodiversity restoration increases the resistance and recovery of ecosystem carbon (C) fluxes to short‐term summer drought. This was tested by measuring plant, soil and microbial responses to a simulated drought in experimental grassland plots where fertilizer application and seed addition have been managed to enhance plant species diversity.

The cessation of fertilizer application brought about small increases in plant species richness. Additionally, cessation of fertilizer application reduced overall plant productivity and promoted hemi‐parasitic plants at the expense of grasses and forbs.

Resistance of CO2 fluxes to drought, measured as ecosystem respiration, was greater in non‐fertilized plots, as lower plant biomass reduced water demand, likely aided by proportionally more hemi‐parasitic plants further reducing plant biomass. Additionally, legumes increased under drought, thereby contributing to overall resistance of plant productivity.

Recovery of soil microbial C and nitrogen was more rapid after rewetting than soil microbial community composition, irrespective of restoration treatment, suggesting high resilience of soil microbial communities to drought.

Synthesis and applications. This study shows that while grassland diversity restoration management increases the resistance of carbon fluxes to drought, it also reduces agricultural yields, revealing a trade‐off for land managers. Furthermore legumes, promoted through long‐term restoration treatments, can help to maintain plant community productivity under drought by increasing their biomass. As such, grassland management strategies not only have consequences for ecosystem processes, but also the capacity to withstand extreme weather events.