bluuebunny/crossref_metadata_2025 huggingface dataset:
Determining Temporal Stability in Dominance Hierarchies
Authors: Vilette C. , Bonnell T.R. , Henzi S.P. , Barrett L
Published: July 2019

The importance of social hierarchies has led to the development of many techniques for inferring social ranks, leaving researchers with an overwhelming array of options to choose from. Many of our research questions involve longitudinal analyses, so we were interested in a method that would provide reliable ranks across time. But how does one determine which method performs best?

We attempt to answer this question by using a training-testing procedure to compare 13 different approaches for calculating dominance hierarchies (seven methods, plus 6 analytical variants of these). We assess each method’s performance, its efficiency, and the extent to which the calculated ranks obtained from the training dataset accurately predict the outcome of observed aggression in the testing dataset.

We found that all methods tested performed well, despite some differences in inferred rank order. With respect to the need for a “burn-in” period to enable reliable ranks to be calculated, again, all methods were efficient and able to infer reliable ranks from the very start of the study period (i.e., with little to no burn-in period). Using a common 6-month burn-in period to aid comparison, we found that all methods could predict aggressive outcomes accurately for the subsequent 10 months. Beyond this 10-month threshold, accuracy in prediction decreased as the testing dataset increased in length. The decay was rather shallow, however, indicating overall rank stability during this period.

In general, a training-testing approach allows researchers to determine the most appropriate method for their dataset, given sampling effort, the frequency of agonistic interactions, the steepness of the hierarchy, and the nature of the research question being asked. Put simply, we did not find a single best method, but our approach offers researchers a valuable tool for identifying the method that will work best for them.

Highlights

All ranking methods tested performed well at predicting future aggressive outcomes, despite some differences in inferred rank order.

All ranking methods appear to be efficient in inferring reliable ranks from the very start (i.e., with little to no burn-in period), but all showed improvement as the burn-in period increased.

Using a common 6-month burn-in period, we found that all methods could predict aggressive outcomes accurately for the subsequent 10 months. Beyond this threshold, accuracy in prediction decreased as the testing dataset increased in length.

Switching to a data-driven approach to assign k-values, via the training/validation/testing procedure, resulted in a marked improvement in performance in the modified Elo-rating method.
Multivariable regulation of gene expression plasticity in metazoans
Authors: Xiao Long , Zhao Zhiguang , He Fei , Du Zhuo
Published: July 2019

An important capacity of genes is the rapid change of expression levels to cope with environment, known as expression plasticity. Elucidating the genomic mechanisms determining expression plasticity is critical for understanding the molecular basis of phenotypic plasticity, fitness, and adaptation. In this study, we systematically quantified genome-wide gene expression plasticity in four metazoan species by integrating changes of expression levels under a large number of genetic and environmental conditions. From this, we demonstrated that expression plasticity measures a distinct feature of gene expression that is orthogonal to other well-studies features including gene expression potential and tissue specificity/broadness. Expression plasticity is conserved across species with important physiological implications. The magnitude of expression plasticity is highly correlated with gene function and genes with high plasticity are implicated in disease susceptibility. Genome-wide analysis identified many conserved promoter cis-elements, trans-acting factors (such as CFCF), and gene body histone modifications (H3K36me3, H3K79me2, and H4K20me1) that are significantly associated with expression plasticity. Analysis of expression changes in perturbation experiments further validated a causal role of specific transcription factors and histone modifications. Collectively, this work reveals general properties, physiological implications, and multivariable regulation of gene expression plasticity in metazoans, extending the mechanistic understanding of gene regulation.
Ohm’s Law for increasing fitness gene expression with selection pressure
Authors: Ciechonska Marta , Sturrock Marc , Grob Alice , Larrouy-Maumus Gerald , Shahrezaei Vahid , Isalan Mark
Published: July 2019

Natural selection relies on genotypic and phenotypic adaptation in response to fluctuating environmental conditions and is the key to predicting and preventing drug resistance. Whereas classic persistence is all-or-nothing, here we show for the first time that an antibiotic resistance gene displays linear dose-responsive selection for increased expression in proportion to rising antibiotic concentration in E. coli. Furthermore, we observe the general nature of an instantaneous phenotypic selection process upon bactericidal and bacteriostatic antibiotic treatment, as well as an amino acid synthesis pathway enzyme under a range of auxotrophic conditions. To explain this phenomenon, we propose an analogy to Ohm’s law in electricity (V=IR) where fitness pressure acts similarly to voltage (V), gene expression to current (I), and resistance (R) to cellular machinery constraints. Lastly, mathematical modelling approaches reveal that the emergent gene expression mechanism requires variation in mRNA and protein production within an isogenic population, and cell ‘memory’ from positive feedbacks between growth and expression of any fitness-inducing gene.
Selective phosphorylation of AKT isoforms in response to dietary cues
Authors: Trautenberg Laura Christin , Prince Elodie , Maas Cornelia , Beier Nora , Honold Freya , Grzybek Michal , Brankatschk Marko
Published: July 2019

A calorie-rich diet is one reason for the continuous spread of metabolic syndromes in western societies. Smart food design is one powerful tool to prevent metabolic stress, and the search for suitable bioactive additives is a continuous task. The nutrient-sensing insulin signaling pathway is an evolutionary conserved mechanism that plays an important role in metabolism, growth and development. Recently, lipid cues capable to stimulate insulin signaling were identified. However, the mechanistic base of their activity remains obscure to date. Here, we show that specific AKT/ Protein kinase B isoforms are responsive to dietary lipid extract compositions and potentiate cellular insulin signaling levels. Our data add a new dimension to existing models and position Drosophila as a powerful model to study the relation between dietary lipid cues and the insulin induced cellular signal cascade.
From injury to full repair: nerve regeneration and functional recovery in the common octopus,Octopus vulgaris
Authors: Imperadore Pamela , Parazzoli Dario , Oldani Amanda , Duebbert Michael , Büschges Ansgar , Fiorito Graziano
Published: July 2019

Spontaneous nerve regeneration in cephalopod molluscs occurs in a relative short time after injury, achieving functional recovery of the lost capacities. In particular, transection of the pallial nerve in the common octopus (Octopus vulgaris) determines loss and subsequent restoring of two functions fundamental for survival, i.e. breathing and skin patterning, the latter involved in communication between animals and concealing. The phenomena occurring after lesion have been investigated in a series of previous studies, but a complete analysis of the changes occurring at the level of the axons and the effects on animals appearance during the whole regenerative process is still missing. Our goal is to determine the course of events following injury. Our goal is to determine the course of events following injury, from impairment to full recovery.

We observed nerve regeneration, end-target re-innervation and functional reconnections between central brain and periphery, using the contralateral nerve in the same animal as internal control. The final architecture of the regenerated nervous tissue does not mirror the original structure, however functionality returns to match the phenotype of an intact octopus, and with no visible impact on the behaviour of the animal. This provides exceptional value to these findings for future studies.

Summary statement

Here we report events occurring after interruption of the peripheral neural circuitry inOctopus vulgaris, from the dramatic loss of normal functioning to full recovery.
A primate-specific retroviral enhancer wires the XACT lncRNA into the core pluripotency network in human
Authors: Casanova Miguel , Moscatelli Madeleine , Chauvière Louis Édouard , Huret Christophe , Samson Julia , Liyakat Ali Tharvesh Moideen , Rosspopoff Olga , Rougeulle Claire
Published: July 2019

Transposable elements (TEs) have been of paramount importance in shaping genomic and epigenomic landscapes of their hosts and in driving the expansion of gene regulatory networks during mammalian evolution. They are found in nearly all long non-coding RNAs (lncRNAs) and have promoted their evolution and function, often in a species- and tissue-specific manner. X-chromosome inactivation (XCI) is an essential process that relies on several TE-enriched lncRNAs. While XCI is conserved across species, one striking difference between human and mouse is the existence of XACT (X active coating transcript), a human-specific lncRNA that coats active X chromosomes in pluripotent cells and may oppose X chromosome silencing in this context. Here, we explore how different families of TEs have contributed to shaping the XACT locus and how they couple its expression to pluripotency in humans. Through a combination of sequence analysis across primates, transcriptional interference and genome editing in human embryonic stem cells (hESCs), we identify a critical enhancer for the transcriptional regulation of the XACT locus that evolved from an ancestral group (LTR48B/ERV1) of mammalian endogenous retroviruses (ERVs), prior to the emergence of XACT. Furthermore, we show that this ancient ERV was hijacked by evolutionarily younger hominoid-specific ERVs that gave rise to the promoter of XACT, thus wiring its expression to the pluripotency network. This work illustrates how retroviral-derived sequences may intervene in species-specific regulatory pathways.
Direct Measurement of Light and Heavy Antibody Chains Using Differential Ion Mobility Spectrometry and Middle-Down Mass Spectrometry
Authors: Melani Rafael D , Srzentić Kristina , Gerbasi Vincent R , McGee John P , Huguet Romain , Fornelli Luca , Kelleher Neil L
Published: July 2019

The analysis of monoclonal antibodies (mAbs) by a middle-down approach is a growing field that attracts the attention of many researchers and biopharma companies. Usually, liquid fractionation techniques are used to separate mAbs polypeptides chains before mass spectrometry (MS) analysis. Gas-phase fractionation techniques such as high-field asymmetric waveform ion mobility spectrometry (FAIMS) can replace liquid-based separations and reduce both analysis time and cost. Here, we present a rapid FAIMS tandem MS method capable of characterizing the polypeptide sequence of mAbs light (Lc) and heavy (Hc) chains in an unprecedented, easy, and fast fashion. This new method uses commercially available instruments and takes ∼ 24 minutes —40-60% faster than regular LC-MS/MS analysis — to acquire fragmentation data using different dissociation methods.
Variations in terrestrial arthropod DNA metabarcoding methods recovers robust beta diversity but variable richness and site indicators based on exact sequence variants
Authors: Porter Teresita M. , Morris Dave M. , Basiliko Nathan , Hajibabaei Mehrdad , Doucet Daniel , Bowman Susan , Emilson Erik J.S. , Emilson Caroline E. , Chartrand Derek , Wainio-Keizer Kerrie , Séguin Armand , Venier Lisa
Published: July 2019

Terrestrial arthropod fauna have been suggested as a key indicator of ecological integrity in forest systems. Because phenotypic identification is expert-limited, a shift towards DNA metabarcoding could improve scalability and democratize the use of forest floor arthropods for biomonitoring applications. The objective of this study was to establish the level of field sampling and DNA extraction replication needed for soil arthropod biodiversity assessments. Processing individually collected field samples recovered significantly higher richness (539-596 ESVs) than pooling the same number of field samples (126-154 ESVs), and we found no significant richness differences when using 1 or 3 pooled DNA extractions. Variations in the number of individual or composite samples or DNA extractions resulted in similar sample clustering based on community dissimilarities. Though our ability to identify taxa to species rank was limited, we were able to use arthropod COI metabarcodes from forest soil to assess richness, distinguish among sites, and recover site indicators based on unnamed exact sequence variants. Our results highlight the need to continue DNA barcoding of local taxa during COI metabarcoding studies to help build reference databases. All together, these sampling considerations support the use of soil arthropod COI metabarcoding as a scalable method for biomonitoring.
Complexity matching: brain signals mirror environment information patterns during music listening and reward
Authors: Carpentier Sarah M. , McCulloch Andrea R. , Brown Tanya M. , Ritter Petra , Wang Zhang , Salimpoor Valorie , Shen Kelly , McIntosh Anthony Randal
Published: July 2019

Understanding how the human brain integrates information from the environment with ongoing, internal brain signals in order to produce individual perspective is an essential element of understanding the human mind. Brain signal complexity, measured with multiscale entropy, has been employed as a measure of information processing in the brain (Carpentier et al., 2016), and we propose that it can also be used to measure the information available from a stimulus. We can directly assess the correspondence, or functional isomorphism, between brain signal complexity and stimulus complexity as an indication of how well the brain reflects the content of the environment in an analysis that we termedcomplexity matching. Music makes an ideal stimulus input because it is a multidimensional, complex signal, and because of its emotion and reward-inducing potential. We found that electroencephalography (EEG) complexity was lower and more closely resembled the musical complexity when participants performed a perceptual task that required them to closely track the acoustics, compared to an emotional task that asked them to think about how the music made them feel. Music-derived reward scores on the Barcelona Music Reward Questionnaire (Mas-Herrero et al., 2013) correlated with worse complexity matching and higher EEG complexity. Compared to perceptual-level processing, emotional and reward responses are associated with additional internal information processes above and beyond those in the external stimulus.

Significance Statement

Experience of our world is combination of the input from the environment, our expectations, and individual responses. For example, the same piece of music can elict happiness in one person and sadness in another. We researched this by measuring the information in pieces of music and whether listener’s brain more closely followed that, or whether additional information was added by the brain. We noted when listener’s were reacting to how music made them feel, their brains added more information and the degree to which this occurred related to how much they find music rewarding. Thus, we were able to provide clues as to how the brain integrates incoming information, adding to it to provide a richer perceptual and emotional experience.
GEOlimma: Differential Expression Analysis and Feature Selection Using Pre-Existing Microarray Data
Authors: Lu Liangqun , Townsend Kevin A. , Daigle Bernie J.
Published: July 2019

Background

Differential expression and feature selection analyses are essential steps for the development of accurate diagnostic/prognostic classifiers of complicated human diseases using transcriptomics data. These steps are particularly challenging due to the curse of dimensionality and the presence of technical and biological noise. A promising strategy for overcoming these challenges is the incorporation of pre-existing transcriptomics data in the identification of differentially expressed (DE) genes. This approach has the potential to improve the quality of selected genes, increase classification performance, and enhance biological interpretability. While a number of methods have been developed that use pre-existing data for differential expression analysis, existing methods do not leverage the identities of experimental conditions to create a robust metric for identifying DE genes.

Results

In this study, we propose a novel differential expression and feature selection method—GEOlimma—which combines pre-existing microarray data from the Gene Expression Omnibus (GEO) with the widely-applied Limma method for differential expression analysis. We first quantify differential gene expression across 2481 pairwise comparisons from 602 curated GEO Datasets, and we convert differential expression frequencies to DE prior probabilities. Genes with high DE prior probabilities show enrichment in cell growth and death, signal transduction, and cancer-related biological pathways, while genes with low prior probabilities were enriched in sensory system pathways. We then applied GEOlimma to four differential expression comparisons within two human disease datasets and performed differential expression, feature selection, and supervised classification analyses. Our results suggest that use of GEOlimma provides greater experimental power to detect DE genes compared to Limma, due to its increased effective sample size. Furthermore, in a supervised classification analysis using GEOlimma as a feature selection method, we observed similar or better classification performance than Limma given small, noisy subsets of an asthma dataset.

Conclusions

Our results demonstrate that GEOlimma is a more effective method for differential gene expression and feature selection analyses compared to the standard Limma method. Due to its focus on gene-level differential expression, GEOlimma also has the potential to be applied to other high-throughput biological datasets.
ATP7B Variant c.1934T>G p.Met645Arg Causes Wilson Disease by Promoting Exon 6 Skipping
Authors: Merico Daniele , Spickett Carl , O’Hara Matthew , Kakaradov Boyko , Deshwar Amit G. , Fradkin Phil , Gandhi Shreshth , Gao Jiexin , Grant Solomon , Kron Ken , Schmitges Frank W. , Shalev Zvi , Sun Mark , Verby Marta , Cahill Matthew , Dowling James J. , Fransson Johan , Wienholds Erno , Frey Brendan J.
Published: July 2019

Wilson Disease is a recessive genetic disorder caused by pathogenic loss-of-function variants in the ATP7B gene. It is characterized by disrupted copper homeostasis resulting in liver disease and/or neurological abnormalities. The variant NM_000053.3:c.1934T>G (Met645Arg) has been reported as compound heterozygous and is highly prevalent among Wilson Disease patients of Spanish descent. Accordingly, it is classified as pathogenic by leading molecular diagnostic centers. However, functional studies suggest that the amino acid change does not alter protein function, leading one ClinVar submitter to question its pathogenicity. Here we used a minigene system and gene-edited HepG2 cells to demonstrate that c.1934T>G causes approximately 70% skipping of exon 6. Exon 6 skipping results in frameshift and stop gain, which is expected to cause loss of ATP7B function. The elucidation of the mechanistic effect for this variant resolves any doubt about its pathogenicity and enables the development of genetic medicines for restoring correct splicing.
Electrical microstimulation evokes saccades in posterior parietal cortex of common marmosets
Authors: Ghahremani Maryam , Johnston Kevin D. , Ma Liya , Hayrynen Lauren K. , Everling Stefan
Published: July 2019

The common marmoset (Callithrix jacchus) is a small-bodied New World primate, increasing in prominence as a model animal for neuroscience research. The lissencephalic cortex of this primate species provides substantial advantages for the application of electrophysiological techniques such as high-density and laminar recordings, which have the capacity to advance our understanding of local and laminar cortical circuits and their roles in cognitive and motor functions. This is particularly the case with respect to the oculomotor system, as critical cortical areas of this network such as the frontal eye fields (FEF) and lateral intraparietal area (LIP) lie deep within sulci in macaques. Studies of cytoarchitecture and connectivity have established putative homologies between cortical oculomotor fields in marmoset and macaque, but physiological investigations of these areas, particularly in awake marmosets, have yet to be carried out. Here, we addressed this gap by probing the function of posterior parietal cortex (PPC) of the common marmoset using electrical microstimulation. We implanted two animals with 32-channel Utah arrays at the location of the putative area LIP and applied microstimulation while they viewed a video display and made untrained eye movements. Similar to previous studies in macaques, stimulation evoked fixed-vector and goal-directed saccades, staircase saccades, and eye blinks. These data demonstrate that area LIP of the marmoset plays a role in the regulation of eye movements, provide additional evidence that this area is homologous with that of the macaque, and further establish the marmoset as valuable model for neurophysiological investigations of oculomotor and cognitive control.

New & Noteworthy

The macaque monkey has been the preeminent model for investigations of oculomotor control, but studies of cortical areas are limited as many of these areas are buried within sulci in this species. Here we applied electrical microstimulation to the putative area LIP of the lissencephalic cortex of awake marmosets. Similar to the macaque, microstimulation evoked contralateral saccades from this area, supporting the marmoset as a valuable model for studies of oculomotor control.
Customizable, engineered substrates for rapid screening of cellular cues
Authors: Huethorst Eline , Cutiongco Marie FA , Campbell Fraser A , Saeed Anwer , Love Rachel , Reynolds Paul M , Dalby Matthew J , Gadegaard Nikolaj
Published: July 2019

Biophysical cues robustly direct cell responses and are thus important tools forin vitroand translational biomedical applications. High throughput platforms exploring substrates with varying physical properties are therefore valuable, however, currently existing platforms are limited in throughput, the biomaterials used, the capability to segregate between different cues and the assessment of dynamic cellular responses. Here we present a multiwell array (3×8) using a substrate engineered with patterns that present topography or rigidity cues welded to a bottomless plate with a 96-well format. Both the patterns on the engineered substrate and the well plate format can be easily customized, permitting systematic and efficient screening of biophysical cues. Here, we demonstrate three multiwell arrays patterned with a variety of topographical and mechanical cues (nano-grooves, soft pillars and nano pillars) tested with three different cell types. Using the multiwell array, we were able to measure cell functionality using analytical modalities such as live microscopy, qPCR and fluorescent immunochemistry. Cardiomyocytes cultured on 5µm grooves showed less variation in electrophysiology and contractile function. Nanopillars with 127 nm height, 100 nm diameter and 300 nm pitch showed improved chondrogenic maintenance from matrix deposition and chondrogenic gene expression. High aspect ratio pillars with an elastic shear modulus of 16 kPa mimicking the cortical bone altered cell adhesion, morphology, and increased expression of osteogenic genes. We have demonstrated the bespoke, controlled and high-throughput properties of the multiwell array that are currently unparalleled in the field today.
Oncoprotein GT198 Vaccination Delays Tumor Growth in MMTV-PyMT Mice
Authors: Achyut Bhagelu R. , Zhang Hao , Angara Kartik , Mivechi Nahid F. , Arbab Ali S. , Ko Lan
Published: July 2019

Different effects of anticancer drugs between mouse and human have caused increasing concerns. A better understanding of cancer initiation between the two species is needed. We have previously identified an oncoprotein GT198 (PSMC3IP) in human breast cancer. In this report, we investigated GT198 in MMTV-PyMT mouse mammary gland tumors and found a reconcilable mechanism in human and mouse. Specifically, distinct tumor initiating stimuli in human and mouse result in a common GT198-mediated tumorigenic pathway in both species. Here we show, similar to human breast cancer even before a tumor appears, GT198 has overexpressed in mouse tumor stroma including pericyte stem cells, descendent adipocytes, fibroblasts, and myoepithelial cells. Using recombinant GT198 protein as an antigen, we vaccinated MMTV-PyMT mice and found that the GT198 vaccine delayed mouse tumor growth and reduced lung metastasis. The antitumor effects in vaccinated mice were linearly correlated with serum titers of GT198 antibody, which can recognize cell surface GT198 protein on viable tumor cells confirmed by FACS. Furthermore, tumor cells isolated from MMTV-PyMT mice were re-implanted into normal FVB/N mice, GT198+tumor cells induced faster tumor growths than GT198-tumor cells. Together, this first study of GT198 vaccine in mouse showed its effectiveness in antitumor and anti-metastasis. The finding may accelerate future development of GT198 immunotherapy in human cancer. Our finding also indicates that even though distinct cancer-initiation stimuli exist between mouse and human, a common tumorigenic pathway mediated by oncoprotein GT198 is shared in both species.
The Impact on Estimations of Genetic Correlations of the Use, in Genome Wide Case-Control Studies, of Super-Normal, Unscreened and Family-History Screened Controls
Authors: Kendler Kenneth S. , Chatzinakos Chris , Bacanu Silviu-Alin
Published: July 2019

Traditionally, in normal case-control studies of disorder A, individuals with disorder A are screened-out of controls. However, in genome wide association (GWA) studies, controls are sometimes unscreened or screened for disorder A and disorder B, producing super-normal controls. Using simulations, we examine how the observed genetic correlations between two disorders (A and B) are influenced by the use of unscreened, normal, and super-normal controls. Normal controls produce unbiased estimates of the genetic correlation. However, unscreened and super-normal controls both bias upward the genetic correlations. The strength of the bias increases with increasing population prevalences for the two disorders. With super-normal controls, the magnitude of bias is stronger when the true genetic correlation is low. The opposite is seen with the use of unscreened controls. Adding screening of first-degree relatives of controls substantially increases the bias in genetic correlations with super-normal controls but has minimal impact when normal controls are used.
Comprehensive analysis of structural and sequencing data reveals almost unconstrained chain pairing in TCRαβ complex
Authors: Shcherbinin Dmitrii S , Belousov Vlad A , Shugay Mikhail
Published: July 2019

Antigen recognition by T-cells is guided by the T-cell receptor (TCR) heterodimer formed by α and β chains. A huge diversity of TCR sequences should be maintained by the immune system in order to be able to mount an effective response towards foreign pathogens, so, due to cooperative binding of α and β chains to the pathogen, any constraints on chain pairing can have a profound effect on immune repertoire structure, diversity and antigen specificity. By integrating available structural data and paired chain sequencing results we were able to show that there are almost no constraints on pairing in TCRαβ complexes, allowing naive T-cell repertoire to reach the highest possible diversity. Additional analysis reveals that the specific choice of contacting amino acids can still have a profound effect on complex conformation. Moreover, antigen-driven selection can distort the uniform landscape of chain pairing, while small, yet significant, differences in the pairing can be attributed to various specialized T-cell subsets such as MAIT and iNKT T-cells, as well as other putative invariant TCRs.
Spider lures exploit insect preferences for floral colour and symmetry
Authors: White Thomas E. , Kemp Darrell J.
Published: July 2019

Sensory systems can capture only a fraction of available information, which creates opportunities for deceptive signalling. The sensory traps and sensory bias models have proven valuable for explaining how visual systems and environments shape the design of sexual signals, but their application to deceptive signals is largely untapped. Here we use the ‘jewelled’ orb-web spiderGasteracantha fornicatato experimentally test two longstanding hypotheses for the function of deceptive visual lures. Namely, that they: (1) exploit generalised preferences for conspicuous colouration (sensory bias), or (2) co-opt the otherwise-adaptive foraging response of prey toward flowers (sensory traps). In a field-based study we manipulated the conspicuous dorsal signal of female spiders along two axes —– colour pattern and symmetry — to generate a gradient of floral resemblance, and monitored the per-individual consequences for prey interception. As predicted by the traps model, the most attractive phenotypes were those with flower-like radial symmetry and solid colour patterns, and their attractiveness equaled that of wild-type models. These results demonstrate that deceptive orb-web spider lures function, in part, as inter-kingdom sensory traps via floral mimicry, and support the broader extension of sensory-based models to deceptive signalling contexts.
Seroprevalence of anti-microbial antibodies in the normal healthy population with implications in chronic diseases
Authors: Zhang Peilin , Minardi Lawrence M. , Kuenstner J. Todd , Zekan Steve M. , Kruzelock Rusty
Published: July 2019

We have previously discovered a panel of anti-microbial antibodies from patients with Crohn’s disease (CD) and Sjogren’s syndrome (Sjo). We have also demonstrated the increase of these anti-microbial antibodies in other autoimmune disease such as rheumatoid arthritis, systemic lupus erythematosus and multiple sclerosis in a small number of cases. The seroprevalence of these antibodies in the normal healthy population is unknown. We set to survey the normal population for these anti-microbial antibodies. We collected 288 blood samples from the donor units of the leukocyte-reduced red blood cells from the American Red Cross, and examined the presence of the anti-microbial antibodies in these blood samples using direct ELISA assays established in our laboratory using the recombinant microbial protein antigens. Our results showed that the prevalence of RPOB antibody in the normal blood donor population is 2.4% (7 positive of 288 samples). The prevalence of EF-G antibody is 4.2% (12 positive of 288 samples), ATP5a 5.2% (15 positive), Hsp65 2.8% (8 positive), EF-Tu 5.6% (16 positive), and NMPC 4.2% (12 positive). Meanwhile, in 109 patients with Crohn’s disease and 28 patients with Sjogren’s syndrome, these anti-bacterial antibodies are significantly increased (p<0.001). These results indicate that the specific anti-microbial antibodies within the normal general population are uncommon, but frequent in chronic disease states. The presence of increased anti-microbial antibodies in the blood of patients but not in normal controls can serve as biomarkers for chronic diseases such as Crohn’s disease and Sjogren’s, and their presence indicates abnormal B-cell/plasma cell function in response to the commensal/pathogenic microbes. Since the antigens were derived from the common microbes present on the surface of the normal population, the antimicrobial antibodies in patients with diseases but not in the normal population suggest a deficient clearance of the microbes from the circulation by the innate immunity system in chronic diseases. These results also raise questions of bacterial vaccination using whole bacterial extracts as these anti-bacterial antibodies appear pathogenic rather than protective, offering fresh thinking in designing bacterial vaccines as preventive or therapeutic measures in chronic diseases such as Crohn’s disease and Sjogren’s Disease.
Mechanism of preferential complex formation by Apoptosis Signal-regulating Kinases
Authors: Trevelyan Sarah J. , Brewster Jodi L. , Burgess Abigail E. , Crowther Jennifer M. , Cadell Antonia L. , Parker Benjamin L. , Croucher David R. , Dobson Renwick C.J. , Murphy James M. , Mace Peter D.
Published: July 2019

Apoptosis signal-regulating kinases (ASK1–3) are activators of the P38 and JNK MAP kinase pathways. ASK1–3 form oligomeric complexes known as ASK signalosomes that initiate signalling cascades in response to diverse stress stimuli. Here we demonstrate that oligomerization of ASK proteins is driven by previously uncharacterised sterile-alpha motif (SAM) domains that reside at the C-terminus of each ASK protein. SAM domains from ASK1–3 have distinct behaviours: ASK1 forms unstable oligomers, ASK2 is predominantly monomeric, and the ASK3 SAM domain forms a stable oligomer even at low concentration. In contrast to their isolated behaviour, the ASK1 and ASK2 SAM domains preferentially form a stable heterocomplex. The crystal structure of the ASK3 SAM domain, small-angle X-ray scattering, and mutagenesis suggests that ASK3 oligomers and ASK1-ASK2 complexes form discrete quasi-helical rings, via the mid-loop–end-helix interface. Preferential ASK1-ASK2 binding is consistent with mass spectrometry showing that full-length ASK1 forms heterooligomeric complexes incorporating high levels of ASK2. Accordingly, disruption of SAM domain-association impairs ASK activity in the context of electrophilic stress induced by 4-hydroxy-2-nonenal. These findings provide a structural template for how ASK proteins assemble foci to drive inflammatory signalling, and reinforce that strategies targeting ASK kinases should consider the concerted actions of multiple ASK family members.
ARPP19 promotes MYC expression and associates with patient relapse in acute myeloid leukemia
Authors: Mäkelä Eleonora , Löyttyniemi Eliisa , Salmenniemi Urpu , Kauko Otto , Varila Taru , Kairisto Veli , Itälä-Remes Maija , Westermarck Jukka
Published: July 2019

Despite of extensive genetic analysis of acute myeloid leukemia (AML), we still do not understand comprehensively mechanism that promote disease relapse from standard chemotherapy. Based on recent indications for non-genomic inhibition of tumor suppressor protein phosphatase 2A (PP2A) in AML, we examined mRNA expression of PP2A inhibitor proteins in AML patient samples. Notably, out of examined PP2A inhibitor proteins, overexpression of ARPP19 mRNA was found independent of current AML risk classification. Functionally, ARPP19 promoted AML cell viability and expression of oncoproteins MYC, CDK1, and another PP2A inhibitor CIP2A. Clinically, ARPP19 mRNA expression was significantly lower at diagnosis (p=0.035) in patients whose disease did not relapse after standard chemotherapy. ARPP19 was an independent predictor for relapse both in univariable (p=0.007) and in multivariable analyses (p=0.0001); and gave additive information to EVI1 expression and risk group status (additive effect, p=0.005). Low ARPP19 expression also associated with better patient outcome in TCGA LAML cohort (p=0.019). In addition, in matched patient samples from diagnosis, remission and relapse phases, ARPP19 expression associated with disease activity (p=0.034).

Together, these data identify ARPP19 as a novel oncogenic PP2A inhibitor protein in AML, and demonstrate its risk group independent role in predicting AML patient relapse tendency.
Prediction of microscopic metastases in patients with metachronous oligo-metastases after curative treatment of Non-Small Cell Lung Cancer
Authors: Wolff H.B. , Alberts L. , Kastelijn E.A. , Verstegen N.E. , El Sharouni S.Y. , Schramel F.M.N.H. , Vos R. , Coupe V.M.H.
Published: July 2019

Metachronous oligo-metastatic disease is variably defined as one to five metastases detected after a disease-free interval and treatment of the primary tumour with curative intent. Oligo-metastases in non-small cell lung cancer (NSCLC) are often treated with curative intent. However additional metastases are often detected later in time, and 5-year survival is low. Burdensome surgical treatment in patients with undetected metastases may be avoided if patients with high versus low-risk of undetected metastases can be separated.

Because there is no clinical data on undetected metastases available, a microsimulation-model of the development and detection of metastases in 100.000 stage I NSCLC patients with a controlled primary tumour was constructed. The model uses data from the literature as well as patient-level data. Calibration was used for unobservable model parameters. Metastases can be detected by a scheduled scan, or an unplanned scan when the patient develops symptoms. The observable information at time of detection is used to identify subgroups of patients with different risk of undetectable metastases. We identified size and number of detected oligo-metastases, as well as presence of symptoms to be the most important risk predictors. Based on these predictors, patients could be divided into a low-risk and a high-risk group having a model-based predicted probability of 8.1% and 89.3% to have undetected metastases, respectively.

Currently, the model is based on a synthesis of literature data and individual patient-level data that was not collected for the purpose of this study. Optimisation and validation of the model is necessary to allow clinical usability. We describe the type of data that needs to be collected to update our model, as well as the design of such validation study.
To mate, or not to mate: The evolution of reproductive diapause facilitates insect radiation into African savannahs in the Late Miocene
Authors: Halali Sridhar , Brakefield Paul M. , Collins Steve C. , Brattström Oskar
Published: July 2019

Many tropical environments experience cyclical seasonal changes, frequently with pronounced wet and dry seasons, leading to a highly uneven temporal distribution of resources. Short-lived animals inhabiting such environments often show season-specific adaptations to cope with alternating selection pressures.

African Bicyclus butterflies show strong seasonal polyphenism in a suite of phenotypic and life-history traits, and their adults are thought to undergo reproductive diapause associated with the lack of available larval host plants during the dry season.

Using three years of longitudinal field data for three species in Malawi, dissections demonstrated that one forest species reproduces continuously whereas two savannah species undergo reproductive diapause in the dry season, either with or without pre-diapause mating. Using additional data from field-collected and museum samples, we then documented the same three mating strategies for a further 37 species.

Phylogenetic analyses indicated that the ancestral state was a non-diapausing forest species, and that habitat preference and mating strategy evolved in a correlated fashion.

Bicyclus butterflies underwent rapid diversification during the Late Miocene, coinciding with expansions into more open savannah habitat. We conclude that the ability to undergo reproductive diapause was a key trait that facilitated colonization and eventual radiation into savannahs in the Late Miocene.
Insights into the bacterial profiles and resistome structures following severe 2018 flood in Kerala, South India
Authors: Divakaran Soumya Jaya , Philip Jamiema Sara , Chereddy Padma , Nori Sai Ravi Chandra , Ganesh Akshay Jaya , John Jiffy , Nelson-Sathi Shijulal
Published: July 2019

Extreme flooding is one of the major risk factors for human health, and it can significantly influence the microbial communities and enhance the mobility of infectious disease agents within its affected areas. The flood crisis in 2018 was one of the severe natural calamities recorded in the southern state of India (Kerala) that significantly affected its economy and ecological habitat. We utilized a combination of shotgun metagenomics and bioinformatics approaches for understanding microbiome disruption and the dissemination of pathogenic and antibiotic-resistant bacteria on flooded sites. Here we report, altered bacterial profiles at the flooded sites having 77 significantly different bacterial genera in comparison with non-flooded mangrove settings. The flooded regions were heavily contaminated with faecal contamination indicators such asEscherichia coliandEnterococcus faecalisand resistant strains ofPseudomonas aeruginosa, SalmonellaTyphi/Typhimurium, Klebsiella pneumoniae, Vibrio choleraeandStaphylococcus aureus. The resistome of the flooded sites contains 103 resistant genes, of which 38% are encoded in plasmids, where most of them are associated with pathogens. The presence of 6 pathogenic bacteria and its susceptibility to multiple antibiotics including ampicillin, chloramphenicol, kanamycin and tetracycline hydrochloride were confirmed in flooded and post-flooded sites using traditional culture-based analysis followed by 16S rRNA sequencing. Our results reveal altered bacterial profile following a devastating flood event with elevated levels of both faecal contamination indicators and resistant strains of pathogenic bacteria. The circulation of raw sewage from waste treatment settings and urban area might facilitate the spreading of pathogenic bacteria and resistant genes.
Learning spatiotemporal signals using a recurrent spiking network that discretizes time
Authors: Maes Amadeus , Barahona Mauricio , Clopath Claudia
Published: July 2019

Learning to produce spatiotemporal sequences is a common task the brain has to solve. The same neural substrate may be used by the brain to produce different sequential behaviours. The way the brain learns and encodes such tasks remains unknown as current computational models do not typically use realistic biologically-plausible learning. Here, we propose a model where a spiking recurrent network of excitatory and inhibitory biophysical neurons drives a read-out layer: the dynamics of the recurrent network is constrained to encode time while the read-out neurons encode space. Space is then linked with time through plastic synapses that follow common Hebbian learning rules. We demonstrate that the model is able to learn spatiotemporal dynamics on a timescale that is behaviourally relevant. Learned sequences are robustly replayed during a regime of spontaneous activity.

Author summary

The brain has the ability to learn flexible behaviours on a wide range of time scales. Previous studies have successfully build spiking network models that learn a variety of computational tasks. However, often the learning involved is not local. Here, we investigate a model using biological-plausible plasticity rules for a specific computational task: spatiotemporal sequence learning. The architecture separates time and space into two different parts and this allows learning to bind space to time. Importantly, the time component is encoded into a recurrent network which exhibits sequential dynamics on a behavioural time scale. This network is then used as an engine to drive spatial read-out neurons. We demonstrate that the model can learn complicated spatiotemporal spiking dynamics, such as the song of a bird, and replay the song robustly.
Juxta-membrane S-acylation of plant receptor-like kinases – fortuitous or functional?
Authors: Hurst Charlotte H. , Wright Kathryn M. , Turnbull Dionne , Leslie Kerry , Jones Susan , Hemsley Piers A.
Published: July 2019

S-acylation is a common post-translational modification of membrane protein cysteine residues with many regulatory roles. S-acylation adjacent to transmembrane domains has been described in the literature as affecting diverse protein properties including turnover, trafficking and microdomain partitioning. However, all of these data are derived from mammalian and yeast systems. Here we examine the role of S-acylation adjacent to the transmembrane domain of the plant pathogen perceiving receptor-like kinase FLS2. Surprisingly, S-acylation of FLS2 adjacent to the transmembrane domain is not required for either FLS2 trafficking or signalling function. Expanding this analysis to the wider plant receptor-like kinase superfamily we find that S-acylation adjacent to receptor-like kinase domains is common but poorly conserved between orthologues through evolution. This suggests that S-acylation of receptor-like kinases at this site is likely the result of chance mutation leading to cysteine occurrence. As transmembrane domains followed by cysteine residues are common motifs for S-acylation to occur, and many S-acyl transferases appear to have lax substrate specificity, we propose that many receptor-like kinases are fortuitously S-acylated once chance mutation has introduced a cysteine at this site. Interestingly some receptor-like kinases show conservation of S-acylation sites between orthologues suggesting that S-acylation has come to play a role and has been positively selected for during evolution. The most notable example of this is in the ERECTA-like family where S-acylation of ERECTA adjacent to the transmembrane domain occurs in all ERECTA orthologues but not in the parental ERECTA-like clade. This suggests that ERECTA S-acylation occurred when ERECTA emerged during the evolution of angiosperms and may have contributed to the neo-functionalisation of ERECTA from ERECTA-like proteins.
Differences in strategic abilities but not associative processes explain memory development
Authors: Müller N.C.J. , Kohn N. , van Buuren M. , Klijn N. , Emmen H. , Berkers R.M.W.J. , Dresler M. , Janzen G. , Fernández G.
Published: July 2019

Children’s learning capabilities change while growing up. One framework that describes the cognitive and neural development of children’s growing learning abilities is the two-component model. It distinguishes processes that integrate separate features into a coherent memory representation (associative component) and executive abilities, such as elaboration, evaluation and monitoring, that support memory processing (strategic component). In an fMRI study using an object-location association paradigm, we investigated how the two components influence memory performance across development. We tested children (10-12 yrs., n=31), late adolescents (18 yrs., n=29) and adults (25+ yrs., n=30) of either sex. For studying the associative component, we also probed how the utilisation of prior knowledge (schemas) facilitates memory across age groups. Children had overall lower retrieval performance, while adolescents and adults did not differ from each other. All groups benefitted from schemas, but this effect did not differ between groups. Performance differences between groups were associated with deactivation of the dorsal medial prefrontal cortex (dmPFC), which in turn was linked to executive functioning. These patterns were stronger in adolescents and adults and seemed absent in children. This pattern of results suggests the children’s executive system, the strategic component, is not as mature and thus cannot facilitate memory performance in the same way as in adolescents/adults. In contrast, we did not find age-related differences in the associative component; with activity in the angular gyrus predicting memory performance systematically across groups. Overall our results suggest that differences of executive rather than associative abilities explain memory differences between children, adolescents and adults.