bluuebunny/crossref_metadata_2025 huggingface dataset:
Novel Pharmacotherapeutics for Stress-Related Disorders
Authors: Mondello Jamie E. , Pak Jenny E. , Lovelock Dennis F. , Deak Terrence
Published: July 2019

Most mental health problems associated with psychological distress originate with activation of centrally regulated stress pathways, yet a diverse range of central nervous system and somatic disease states can be influenced by exposure to severe or unrelenting stress. The goal of this chapter is to provide a conceptual framework to guide the development of pharmacological intervention strategies. We propose that careful consideration of the relationship between the timing of stressful life experiences, pharmacological intervention, and the ultimate expression of disease symptomatology is critical for the development of pharmacological interventions to treat stress-related disorders. We review a range of physiological systems that are known to be activated by stress, offering potentially new targets for drug development efforts, and argue that participant selection is a key predictor of drug efficacy trials. In doing so, we point toward inflammatory signaling pathways as a potential final common mediator of multiple stress-related disease states.
Stress in Schizophrenia
Authors: Goines Katrina , Macdonald LoPilato Allison , Novacek Derek , España Roberto , Walker Elaine
Published: July 2019

This chapter contains a review and discussion of evidence linking various types of psychosocial stress with the onset and course of schizophrenia and other psychotic disorders. Stress has long been considered an important factor in the etiology of psychosis and psychotic disorders. Specifically, stress is thought to interact with pre-existing biological vulnerabilities to trigger psychosis through complex changes to various biological processes (e.g., changes to HPA axis, neurotransmitter activity, and inflammatory processes). This chapter includes discussion of a wide variety of stress experiences, including daily hassles, life events, trauma, childhood adversity, and minority stress, and explores the scientific evidence linking these stressors with psychosis and psychotic disorders. Biological processes and biomarkers associated with both stress and psychosis are also discussed. Finally, important questions relating to the future study of stress and psychosis are considered.
Validity of Physical Exam Maneuvers in the Diagnosis of Sacroiliac Joint Pathology
Authors: Schneider Byron J , Ehsanian Reza , Rosati Renee , Huynh Lisa , Levin Josh , Kennedy David J
Published: July 2019

Background

A combination of physical examination maneuvers is currently considered necessary to help predict who will respond to injections in the sacroiliac joint. However, the literature on this topic currently consists of conflicting studies, with one showing the value of a combination of exam maneuvers and the other showing no real value.

Objective

To determine the diagnostic validity of sacroiliac joint (SIJ) physical exam maneuvers using anesthetic intra-articular injection as a reference standard.

Design

A single institution prospective study.

Participants

Patients with the clinical diagnosis of SIJ pain and referred for SIJ injection were enrolled.

Main Outcome Measure

Numeric rating scale (NRS) to assess pain intensity

Results

Participants underwent fluoroscopically guided SIJ intra-articular injection with 1 cc of 2% lidocaine and 1 cc of triamcinolone 40 mg. Patients’ pain was assessed via 0–10 NRS pre-injection and immediately postinjection to determine positive anesthetic response to the injection. Six physical exam maneuvers (thigh thrust, Geanslen’s test, FABER test, distraction test, compression test, and sacral thrust) were performed pre-injection and 15 minutes postinjection. The results of these SIJ physical exam maneuvers were evaluated singly and in combinations for diagnostic power in relation to a positive anesthetic response (>80% relief) to the injection. No association was found between a single SIJ physical exam maneuver or combination of maneuvers and anesthetic response to the injection.

Conclusions

In this cohort, patient physical exam maneuvers to identify intra-articular SIJ pain did not demonstrate diagnostic value when compared with the reference standard of an intra-articular anesthetic block.
Relationships between objectives sleep parameters and brain amyloid load in subjects at risk for Alzheimer’s disease: the INSIGHT-preAD Study
Authors: Ettore Eric , Bakardjian Hovagim , Solé Marine , Levy Nogueira Marcel , Habert Marie-Odile , Gabelle Audrey , Dubois Bruno , Robert Philippe , David Renaud
Published: July 2019

Study Objectives

Sleep changes have been associated with increased risks of developing cognitive disturbances and Alzheimer’s disease (AD). A bidirectional relation is underlined between amyloid-beta (Aß) and sleep disruptions. The sleep profile in participants at risk to develop AD is not fully deciphered. We aim to investigate sleep–wake changes with objective sleep measurements in elderly participants without cognitive impairment depending on their brain amyloid status, positive (Aß+) or negative (Aß−) based on standard absorption ratios (SUVr) positron emission tomography-florbetapir imaging.

Methods

Sixty-eight participants without cognitive impairment who have accepted to be involved in the sleep ancillary study from the InveStIGation of Alzheimer’s Predictors in Subjective Memory Complainers (INSIGHT-pre AD) cohort, aiming to record sleep profile based on the analyses of an ambulatory accelerometer-based assessment (seven consecutive 24-hour periods). Neuropsychological tests were performed and sleep parameters have been individualized by actigraph. Participants also underwent a magnetic resonance imaging scan to assess their hippocampal volume. Based on SUVr PET-florbetapir imaging, two groups Aß+ and Aß− were compared.

Results

Participants were divided into two groups: Aß+ (n = 24) and Aß− (n = 44). Except for the SUVr, the two subgroups were comparable. When looking to sleep parameters, increased sleep latency, sleep fragmentation (wake after sleep onset [WASO] score and awakenings) and worst sleep efficiency were associated with cortical brain amyloid load.

Conclusion

Actigraphic sleep parameters were associated with cortical brain amyloid load in participants at risk to develop AD. The detection of sleep abnormalities in those participants may be of interest to propose some preventive strategies.
The Modification of the Flavonoid Naringenin by Bradyrhizobium sp. Strain ORS285 Changes the nod Genes Inducer Function to a Growth Stimulator
Authors: Nouwen Nico , Gargani Daniel , Giraud Eric
Published: July 2019

As inducers of nodulation (nod) genes, flavonoids play an important role in the symbiotic interaction between rhizobia and legumes. However, in addition to the control of expression of nod genes, many other effects of flavonoids on rhizobial cells have been described. Here, we show that the flavonoid naringenin stimulates the growth of the photosynthetic Bradyrhizobium sp. strain ORS285. This growth-stimulating effect was still observed for strain ORS285 with nodD1, nodD2, or the naringenin-degrading fde operon deleted. Phenotypic microarray analysis indicates that in cells grown in the presence of naringenin, the glycerol and fatty acid metabolism is activated. Moreover, electron microscopic and enzymatic analyses show that polyhydroxy alkanoate metabolism is altered in cells grown in the presence of naringenin. Although strain ORS285 was able to degrade naringenin, a fraction was converted into an intensely yellow-colored molecule with an m/z (+) of 363.0716. Further analysis indicates that this molecule is a hydroxylated and O-methylated form of naringenin. In contrast to naringenin, this derivative did not induce nod gene expression, but it did stimulate the growth of strain ORS285. We hypothesize that the growth stimulation and metabolic changes induced by naringenin are part of a mechanism to facilitate the colonization and infection of naringenin-exuding host plants.
Intraspecific population admixture of a top piscivore correlates with anthropogenic alteration of freshwater ecosystems
Authors: Eschbach Erik , Nolte Arne Wolfram , Kohlmann Klaus , Alos Josep , Schöning Sandro , Arlinghaus Robert
Published: July 2019

Conservation of local genetic diversity is an important policy objective, but intraspecific genetic diversity can be transformed by natural ecological processes associated with anthropogenic changes in ecosystems. Environmental changes and a strong interconnection of drainage systems impact freshwater biodiversity from gene to population level. Populations can either become extinct or expand their range and accompanying secondary contacts can lead to genetic admixture. We investigated how the genetic population structure and the patterns of genetic admixture ofEsox luciusL. (the northern pike) vary with the type of ecosystem and the integrity of the ecosystem assessed by measures under the European Water Framework Directive. The pike inhabits river, lake and brackish water ecosystems, where it is confronted with different ecological disturbances. We analysed 1,384 pike samples from the North, Baltic and Black Sea drainages and differentiated between metapopulations from each hydrogeographic region using genotypes from 15 microsatellites and mitochondrialcyt bsequences. Individual populations showed signs of genetic admixture ranging from almost zero to complete replacement by foreign genotypes. Hierarchical general linear modeling revealed a highly significant positive association of the degree of genetic admixture with decreasing ecological status. This may mean that populations in disturbed environments are more prone to influences by foreign genotypes or, alternatively, increased genetic admixture may indicate adaptation to rapid environmental changes. Regardless of the underlying mechanisms, our results suggest that anthropogenic alterations of natural freshwater ecosystems can influence genetic structures, which may lead to a large-scale reduction of intraspecific genetic diversity.
Specific targeting of intestinalPrevotella copriby aListeria monocytogenesbacteriocin
Authors: Rolhion Nathalie , Chassaing Benoit , Nahori Marie-Anne , de Bodt Jana , Moura Alexandra , Lecuit Marc , Dussurget Olivier , Bérard Marion , Marzorati Massimo , Fehlner-Peach Hannah , Littman Dan R. , Gewirtz Andrew T. , Van de Wiele Tom , Cossart Pascale
Published: July 2019

Deciphering the specific function of every microorganism in microbial gut communities is a key issue to interrogate their role during infection. Here, we report the discovery of aListeriabacteriocin, Lmo2776, that specifically targets the abundant gut commensalPrevotella copriand affectsListeriainfection. Oral infection of conventional mice with a Δlmo2776mutant leads to a thinner intestinal mucus layer and higherListerialoads both in the intestinal content and deeper tissues compared to WTListeria, while no difference is observed in germ-free mice. This microbiota-dependent effect is phenocopied by precolonization of germ-free mice beforeListeriainfection, withP. copri, but not with other commensals,. Together, these data unveil a role forPrevotellain controlling intestinal infection, highlighting that pathogens may selectively deplete microbiota to avoid excessive inflammation.
Mesenchymal stem cells therapy for spinal cord contusion: a comparative study on small and large animal models
Authors: Mukhamedshina Yana , Shulman Iliya , Ogurcov Sergei , Kostennikov Alexander , Zakirova Lena , Akhmetzyanova Elvira , Rogozhin Alexander , Masgutova Galina , James Victoria , Masgutov Ruslan , Lavrov Igor , Rizvanov Albert
Published: July 2019

Here, we provided a first comparative study of the therapeutic potential of allogeneic mesenchymal stem cells derived from bone marrow (BM-MSCs), adipose tissue (AD-MSCs), and dental pulp (DP-MSCs) embedded in fibrin matrix in a small (rat) and large (pig) spinal cord injury (SCI) model during sub-acute period of spinal contusion. Results of behavioral, electrophysiological, histological assessment, as well as results of immunohistochemistry and RT-PCR analysis suggest that application of AD-MSCs combined with a fibrin matrix in a subacute period in rats (2 weeks after injury) provides significantly higher post-traumatic regeneration compared to a similar application of BM-MSCs or DP-MSCs. Within the rat model, use of AD-MSCs resulted in a marked change in (1) restoration of locomotor activity and conduction along spinal axons, (2) reduction of post-traumatic cavitation and enhancing tissue retention, and (3) modulation of microglial and astroglial activation. The effect of therapy with an autologous application of AD-MSCs was also confirmed in subacute period after spinal contusion in pigs (6 weeks after injury), however, with only partial replication of the findings observed in rats, i.e. (1) partial restoration of the somatosensory spinal pathways, (2) reduction of post-traumatic cavitation and enhancing tissue retention, and (3) modulation of astroglial activation in dorsal root entry zone. The results of this study suggest that application of AD-MSCs embedded in fibrin matrix at the site of SCI during the subacute period can facilitate regeneration of nervous tissue in rats and pigs. These results, for the first time, provide robust support for the use of AD-MSC to treat subacute SCI.
Type I interferons are important co-stimulatory signals during T cell receptor mediated MAIT cell activation
Authors: Lamichhane Rajesh , Galvin Henry , Hannaway Rachel F , de la Harpe Sara M , Munro Fran , Tyndall Joel DA , Vernall Andrea J , McCall John L , Husain Matloob , Ussher James E
Published: July 2019

Mucosal associated invariant T (MAIT) cells are abundant unconventional T cells which can be stimulated either via their T cell receptor (TCR) or by innate cytokines. The MAIT cell TCR recognises a pyrimidine ligand, derived from riboflavin synthesising bacteria, bound to MR1. In infection, bacteria not only provide the pyrimidine ligand but also co-stimulatory signals, such as Toll-like receptor agonists, that can modulate TCR-mediated activation. Recently, type I interferons (T1-IFNs) have been identified as contributing to cytokine-mediated MAIT cell activation. However, it is unknown whether T1-IFNs also have a role during TCR-mediated MAIT cell activation. In this study, we investigated the co-stimulatory role of T1-IFNs during TCR-mediated activation of MAIT cells by the MR1 ligand 5-amino-6-D-ribitylaminouracil/methylglyoxal (5-A-RU/MG). We found that T1-IFNs were able to boost interferon-γ and granzyme B production in 5-A-RU/MG-stimulated MAIT cells. Similarly, influenza virus-induced T1-IFNs enhanced TCR-mediated MAIT cell activation. An essential role of T1-IFNs in regulating MAIT cell activation by riboflavin synthesising bacteria was also demonstrated. The co-stimulatory role of T1-IFNs was confirmed using liver-derived MAIT cells. T1-IFNs acted directly on MAIT cells to enhance their response to TCR stimulation. Overall, our findings establish an important immunomodulatory role of T1-IFNs during TCR-mediated MAIT cell activation.
Joint Motion Estimation and Source Identification using Convective Regularisation with an Application to the Analysis of Laser Nanoablations
Authors: Lang Lukas F. , Dutta Nilankur , Scarpa Elena , Sanson Bénédicte , Schönlieb Carola-Bibiane , Étienne Jocelyn
Published: July 2019

We propose a variational method for joint motion estimation and source identification in one-dimensional image sequences. The problem is motivated by fluorescence microscopy data of laser nanoablations of cell membranes in live Drosophila embryos, which can be conveniently—and without loss of significant information—represented in space-time plots, so called kymographs. Based on mechanical models of tissue formation, we propose a variational formulation that is based on the nonhomogenous continuity equation and investigate the solution of this ill-posed inverse problem using convective regularisation. We show existence of a minimiser of the minimisation problem, derive the associated Euler–Lagrange equations, and numerically solve them using a finite element discretisation together with Newton’s method. Based on synthetic data, we demonstrate that source estimation can be crucial whenever signal variations can not be explained by advection alone. Furthermore, we perform an extensive evaluation and comparison of various models, including standard optical flow, based on manually annotated kymographs that measure velocities of visible features. Finally, we present results for data generated by a mechanical model of tissue formation and demonstrate that our approach reliably estimates both a velocity and a source.
Bach2 is a potent repressor of Nrf2-mediated antioxidant enzyme expression in dopaminergic neurons
Authors: Waxman Elisa A.
Published: July 2019

Nuclear factor erythroid 2–related factor 2 (Nrf2) is a transcriptional activator of antioxidant response elements (ARE), which function to increase expression of antioxidant enzymes. Recent works suggests Nrf2 activation is a promising protective mechanism against the progressive neurodegeneration in Parkinson’s disease (PD). While Nrf2 inducers show some promising results in animal models of PD, the response is limit in dopaminergic neurons with the protection mostly conferred by surrounding glia. The present study characterizes ARE transcriptional repressors Bach1 and Bach 2 (Broad complex– Tramtrack–Bric-a-brac and Cap n’ Collar homology, basic leucine zipper transcription factors 1 and 2) as a potential explanation for limited Nrf2 activity in these neurons. The current work identified Bach1 and Bach2 in dopaminergic neurons of the human substantia nigra by immunocytochemical analyses. We further identified Bach2 as a more robust inhibitor of Nrf2 responses. The effects of both Bach1 and Bach2 were dependent on their DNA-binding domains, but the DNA-binding domains did not entirely explain the differences in their relative repressor activities. Using IMR-32 neuroblastoma cells, we found differentiation into a dopaminergic neuronal phenotype resulted in increased Bach2 expression, decreased full-length Bach1 expression, increased truncated Bach1, and blunted Nrf2-mediated responses. Bach inhibitors cobalt protoporphyrin or cadmium chloride, which were more effective against Bach1 than Bach2, did not rescue Nrf2 responses. These results provide a novel mechanism for the lack of antioxidant responses and sensitivity of dopaminergic neurons to oxidative damage, in addition to proposing Bach2 as a novel drug target for the treatment of PD.

Significance

Oxidative stress and damage are unifying contributors to explain the progressive loss of dopaminergic neurons in Parkinson’s disease (PD). Although increased transcription of antioxidant enzymes by nuclear factor erythroid 2-related factor 2 (Nrf2) shows potential in combating oxidative damage, Nrf2 protection is mostly conferred by surrounding glia with a relative inability of neurons to mount a protective response. This work characterizes transcriptional repressors Bach1 and Bach2 that inhibit Nrf2 responses and prevent antioxidant enzyme production. This study supports Bach2 as a major factor in preventing antioxidant production in neurons and as a novel drug target to protect against PD.
Shortening injection matrix for serial crystallography
Authors: Nam Ki Hyun
Published: July 2019

Serial crystallography (SX) allows crystal structures to be observed at room temperature through the steady delivery of crystals to the X-ray interaction point. Viscous delivery media are advantageous because they afford efficient sample delivery from an injector or syringe at a low flow rate. Hydrophobic delivery media, such as lipidic cubic phase (LCP) or grease, provide a very stable injection stream and are widely used. The development of new hydrophobic delivery materials can expand opportunities for future SX studies with various samples. Here, I introduce fat-based shortening as a delivery medium for SX experiments. This material is commercially available at low cost and is straightforward to handle because its phase (i.e., solid or liquid) can be controlled by temperature. Shortening was extruded from a syringe needle in a very stable injection stream even below 200 nl/min. X-ray exposed shortening produced several background scattering rings, which have similar or lower intensities than those of LCP and contribute negligibly to data processing. Serial millisecond crystallography was performed using two shortening delivery media, and the room temperature crystal structures of lysozyme and glucose isomerase were successfully determined at resolutions of 1.5–2.0 Å. Therefore, shortening can be used as a sample delivery medium in SX experiments.
A large single-participant fMRI dataset for probing brain responses to naturalistic stimuli in space and time
Authors: Seeliger K. , Sommers R. P. , Güçlü U. , Bosch S. E. , van Gerven M. A. J.
Published: July 2019

Visual and auditory representations in the human brain have been studied with encoding, decoding and reconstruction models. Representations from convolutional neural networks have been used as explanatory models for these stimulus-induced hierarchical brain activations. However, none of the fMRI datasets currently available has adequate amounts of data for sufficiently sampling their representations. We recorded a densely sampled large fMRI dataset (TR=700 ms) in a single individual exposed to spatiotemporal visual and auditory naturalistic stimuli (30 episodes of BBC’s Doctor Who). The data consists of 120.830 whole-brain volumes (approx. 23 h) of single-presentation data (full episodes, training set) and 1.178 volumes (11 min) of repeated narrative short episodes (test set, 22 repetitions), recorded with fixation over a period of six months. This rich dataset can be used widely to study the way the brain represents audiovisual input across its sensory hierarchies.
Predictive and Aetiological Potential of Polygenic Strata with Extreme and Moderate Disease Risks Predictions:Case Study of Coeliac Disease GWAS
Authors: Kowalczyk Adam
Published: July 2019

We show by using example of coeliac disease (CD) that a genomic risk assessment could significantly improve efficiency of disease diagnosing. It can detect novel highly deleterious rare variants (penetrance 100%, frequency ∼1:6,700) as well as common protective variants (penetrance 0.03%, frequency ∼1:3). However, the major translational gains with potential for multi-billion-dollar cost savings in Australia or USA alone, could be in assessing patients in cohorts with moderately elevated CD risk (3% −10%) exhibiting clinical symptoms or with family history of CD. The gains result from judicious re-direction of expensive confirmatory testing towards ∼30% of the cohort with the highest likelihood of the condition (∼90% of cohort CD cases), while avoiding costs, inconvenience and risk of side-complications for the remaining majority of ∼70%.

We build our estimates using concrete results of CD Genome Wide Association Studies (GWAS) already in the public domain1–4. The largest of five Genomic Risk Score (GRS) models1considered here deploys 228 directly genotyped Simple Nucleotide Polymorphisms (SNPs), while the simplest2uses only 6 SNPs. Thus, a DNA profile supporting all these models can be easily accommodated on any commodity, Direct-to-Consumer5(DTC), saliva-based genotyping platform. Once generated, such a generic profile of over 600,000 SNPs could assist medical practitioners in diagnosing this as well as thousands of other diseases on demand, virtually genotyping cost free.
Gene Transfer Agents in Plant Pathogenic Bacteria: Comparative Mobilomics, Genomic Survey and Recombinogenic Impacts
Authors: Jibrin Mustafa O. , Minsavage Gerald V. , Goss Erica M. , Roberts Pamela D. , Jones Jeffrey B.
Published: July 2019

Background

Gene transfer agents (GTAs) are phage-like mediators of gene transfer in bacterial species. Typically, strains of a bacteria species which have GTA shows more recombination than strains without GTAs. GTA-mediated gene transfer activity has been shown for few bacteria, with Rhodobacter capsulatus being the prototypical GTA. GTA have not been previously studied in plant pathogenic bacteria. A recent study inferring recombination in strains of the bacterial spot xanthomonads identified a Nigerian lineage which showed unusual recombination background. We initially set out to understand genomic drivers of recombination in this genome by focusing on mobile genetic elements.

Results

We identified a unique cluster which was present in the Nigerian strain but absent in other sequenced strains of bacterial spot xanthomonads. The protein sequence of a gene within this cluster contained the GTA_TIM domain that is present in bacteria with GTA. We identified GTA clusters in other Xanthomonas species as well as species of Agrobacterium and Pantoea. Recombination analyses showed that generally, strains of Xanthomonas with GTA have more inferred recombination events than strains without GTA, which could lead to genome divergence.

Conclusion

This study identified GTA clusters in species of the plant pathogen genera Xanthomonas, Agrobacterium and Pantoea which we have named XpGTA, AgGTA and PaGTA respectively. Our recombination analyses suggest that Xanthomonas strains with GTA generally have more inferred recombination events than strains without GTA. The study is important in understanding the drivers of evolution of bacterial plant pathogens.
High-throughput phenotyping reveals expansive genetic and structural underpinnings of immune variation
Authors: Abeler-Dörner Lucie , Laing Adam G. , Lorenc Anna , Ushakov Dmitry S. , Clare Simon , Speak Anneliese , Duque Maria , White Jacqui K. , Ramirez-Solis Ramiro , Saran Namita , Bull Katherine R. , Morón Belén , Iwasaki Jua , Barton Philippa R. , Caetano Susana , Hng Keng I. , Cambridge Emma , Forman Simon , Crockford Tanya L. , Griffiths Mark , Kane Leanne , Harcourt Katherine , Brandt Cordelia , Notley George , Babalola Kolawole O. , Warren Jonathan , Mason Jeremy C. , Meeniga Amrutha , Karp Natasha A. , Melvin David , Cawthorne Eleanor , Weinrick Brian , Rahim Albina , Drissler Sibyl , Meskas Justin , Yue Alice , Lux Markus , Song-Zhao George , Chan Anna , Reviriego Carmen Ballesteros , Abeler Johannes , Wilson Heather , Przemska-Kosicka Agnieszka , Edmans Matthew , Strevens Natasha , Pasztorek Markus , Meehan Terrence F. , Powrie Fiona , Brinkman Ryan , Dougan Gordon , Jacobs William , Lloyd Clare , Cornall Richard J. , Maloy Kevin , Grencis Richard , Griffiths Gillian M. , Adams David , Hayday Adrian C.
Published: July 2019

By developing a high-density murine immunophenotyping platform compatible with high-throughput genetic screening, we have established profound contributions of genetics and structure to immune variation. Specifically, high-throughput phenotyping of 530 knockout mouse lines identified 140 monogenic “hits” (>25%), most of which had never hitherto been implicated in immunology. Furthermore, they were conspicuously enriched in genes for which humans show poor tolerance to loss-of-function. The immunophenotyping platform also exposed dense correlation networks linking immune parameters with one another and with specific physiologic traits. By limiting the freedom of individual immune parameters, such linkages impose genetically regulated “immunological structures”, whose integrity was found to be associated with immunocompetence. Hence, our findings provide an expanded genetic resource and structural perspective for understanding and monitoring immune variation in health and disease.
Unbiased analysis of C. elegans behavior reveals the use of distinct turning strategies during magnetic Orientation
Authors: Bainbridge C , McDonald J , Ahlert A. , Benefield Z , Stein W , Vidal-Gadea AG
Published: July 2019

To successfully navigate their surroundings, animals detect and orient to environmental stimuli possessing unique physical properties. Most animals can derive directional information from spatial or temporal changes in stimulus intensity (e.g. chemo- and thermo-taxis). However, some biologically relevant stimuli have constant intensity at most organismal scales. The gravitational and magnetic fields of the earth are examples of uniform stimuli that remain constant at most relevant scales. While devoid of information associated with intensity changes, the vectorial nature of these fields intrinsically encodes directional information. While much is known about behavioral strategies that exploit changes in stimulus intensity (gradients), less is understood about orientation to uniform stimuli. Nowhere is this truer than with magnetic orientation. While many organisms are known to orient to the magnetic field of the earth, how these animals extract information from the earth’s magnetic field remains unresolved.

Here we use the nematode C. elegans to investigate behavioral strategies for orientation to magnetic fields, and compare our findings to the better characterized chemical and thermal orientation strategies. We used an unbiased cluster analysis to categorize, quantify, and compare behavioral components underlying different orientation strategies as a way to quantify and compare animal orientation to distinct stimuli. We find that in the presence of an earth-like magnetic field, worms perform acute angle turns (140-171°) that significantly improved their alignment with the direction of an imposed magnetic vector. In contrast, animals performed high amplitude turns (46-82°) that significantly increased alignment of their trajectory with the preferred migratory angle. We conclude that C. elegans orients to earth-strength magnetic fields using two independent behavioral strategies, in contrast to orientation strategies to graded stimuli. Understanding how C. elegans detects and orients to magnetic fields will provide useful insight into how many species across taxa accomplish this fascinating sensory feat.
Targeted enhancement of the therapeutic window of L19-TNF by transient and selective inhibition of RIPK1-signaling cascade
Authors: Dakhel Sheila , Ongaro Tiziano , Gouyou Baptiste , Matasci Mattia , Villa Alessandra , Neri Dario , Cazzamalli Samuele
Published: July 2019

Introduction

Cytokine-based products are gaining importance for cancer immunotherapy. L19-TNF is a clinical-stage antibody-cytokine fusion protein that selectively accumulates to tumors and displays potent anticancer activity in preclinical models. Here, we describe an innovative approach to transiently inhibit off-target toxicity of L19-TNF, while maintaining antitumor activity.

Methods

GSK’963, a potent small molecule inhibitor of RIPK1, was tested in tumor-bearing mice for its ability to reduce acute toxicity associated with TNF signaling. The biological effects of L19-TNF on tumor cells, lymphocytes and tumor vessels were investigated with the aim to enable the administration of TNF doses, which would otherwise be lethal.

Results

Transient inhibition of RIPK1 allowed to increase the maximal tolerated dose of L19-TNF. The protective effect of GSK’963 did not affect the selective localization of the immunocytokine to tumors as evidenced by quantitative biodistribution analysis and allowed to reach high local TNF concentrations around tumor blood vessels, causing diffused vascular shutdown and hemorrhagic necrosis within the neoplastic mass.

Conclusions

The selective inhibition of RIPK1 with small molecule inhibitors can be used as a pharmaceutical tool to transiently mask TNF activity and improve the therapeutic window of TNF-based biopharmaceuticals. Similar approaches may be applicable to other pro-inflammatory cytokines.
Invasion but not hybridisation is associated with ecological niche shift in monkeyflowers
Authors: Da Re Daniele , Olivares Angel P. , Smith William , Vallejo-Marín Mario
Published: July 2019

Background

The ecological niche occupied by novel hybrids can influence their establishment as well as the potential to coexist with their parents. Hybridisation generates new phenotypic combinations, which, in some cases, may allow them to occupy ecological niches outside the environmental envelope of parental taxa. In other cases, hybrids may retain similar ecological niches to their parents, resulting in competition and affecting their coexistence. To date, few studies have quantitatively assessed niche shifts associated with hybridisation in recently introduced populations while simultaneously characterising the niche of parental species in both native and introduced ranges.

Aims

In this study, we compared the ecological niche of a novel hybrid plant with the niches of its two parental taxa in the non-native geographic range. We also characterised and compared the parental taxa’s ecological niche of native and introduced populations in order to assess potential niche changes during the invasion process independent of hybridisation.

Methods

We studied monkeyflowers (Mimulus spp., Phrymaceae) that were introduced from the Americas to Europe and New Zealand in the last 200 years. We focused on a novel hybrid, triploid, asexual taxon (M. × robertsii) that occurs only in the British Isles where its two parents (M. guttatusandM. luteus) come into secondary contact. We assembled more than 12,000 geo-referenced occurrence records and eight environmental variables of the three taxa across native and introduced ranges, and conducted ecological niche model analysis using maximum entropy, principal component and niche dynamics analysis.

Results

We found no evidence of niche shift in the hybrid,M. × robertsiicompared to introduced populations of both of their parental taxa. The hybrid had a niche more similar toM. luteus, which is also the rarest of the parental taxa on the introduced range. Among parental monkeyflowers,M. guttatusshowed niche conservatism in introduced populations in Europe, but a niche shift in New Zealand, whileM. luteusshowed a niche shift in Europe. However, the evidence of niche shift should be treated with caution due to the occurence of non-analog climatic conditions, small population size and unfilling niche dynamics.

Conclusions

Our results suggest that hybridisation in non-native monkyeflowers did not result in a shift in ecological niche. This niche conservation could create competition between parental and derived taxa, the outcome of which will depend on relative competitive abilities. Further work is needed to establish if the expansion of the hybrid in the introduced range is causally related to the apparent rarity of one of the parents (M.luteus). Finally, the comparison of native and non-native populations of parental taxa, suggest that whether invasions result in niche shifts or not depends on both taxon and geographic region, highlighting the idiosyncratic nature of biological invasions.
Time spent in distinct life-history stages has sex-specific effects on reproductive fitness in wild Atlantic salmon
Authors: Mobley Kenyon B. , Granroth-Wilding Hanna , Ellmen Mikko , Orell Panu , Erkinaro Jaakko , Primmer Craig R.
Published: July 2019

In species with complex life cycles, life history theory predicts that fitness is affected by conditions encountered in previous life history stages. Here, we use a four-year pedigree to investigate if time spent in two distinct life history stages has sex-specific reproductive fitness consequences in anadromous Atlantic salmon (Salmo salar). We determined the amount of years spent in fresh water as juveniles (freshwater age, FW), and years spent in the marine environment prior to sexual maturation (sea age, SW) on 264 spawning adults. We then estimated reproductive fitness as the number of offspring (reproductive success) and the number of mates (mating success) using genetic parentage analysis (>5000 offspring). Sea age is positively correlated with reproductive and mating success of both sexes whereby older and larger individuals gained the highest reproductive fitness benefits (females: increase of 16.5 offspring/SW and 0.86 mates/SW; males: increase of 12.4 offspring/SW and 0.43 mates/SW). Younger freshwater age was related to older sea age and thus increased reproductive fitness, but only among females (females: −9.0 offspring/FW and −0.80 mates/FW). This implies that females can obtain higher reproductive fitness by transitioning to the marine environment earlier. In contrast, male mating and reproductive success was unaffected by freshwater age and males returned to spawn earlier than females despite the fitness advantage of later sea age maturation. Our results show that the timing of transitions between juvenile and adult phases has a sex-specific consequence on female reproductive fitness, demonstrating a life-history trade-off between maturation and reproduction in wild Atlantic salmon.
Effects of treatment with enrofloxacin or tulathromycin on fecal microbiota composition and function of dairy calves
Authors: Foditsch Carla , Pereira Richard V.V. , Siler Julie D. , Altier Craig , Warnick Lorin D.
Published: July 2019

The increasing concerns with antimicrobial resistance highlights the need for studies evaluating the impacts of antimicrobial use in livestock on antimicrobial resistance using new sequencing technologies. Through shotgun sequencing, we investigated the changes in the fecal microbiome composition and function, with a focus on functions related to antimicrobial resistance, of dairy calves. Heifers 2 to 3 weeks old, which were not treated with antibiotics by the farm before enrollment, were randomly allocated to one of three study groups: control (no treatment), enrofloxacin, or tulathromycin. Fecal samples were collected at days 4, 14, 56 and 112 days after enrollment, and DNA extraction and sample preparation and sequencing was conducted. The effect of antibiotic treatment on each taxon and functional level by time (including Day 0 as a covariate) revealed few changes in the microbiota. At the genus level, enrofloxacin group had higher abundance of Blautia, Coprococcus and Desulfovibrio and lower abundance of Bacteroides when compared to other treatment groups. The SEED database was used for functional analyses, which showed that calves in the enrofloxacin group started with a higher abundance of “Resistance to antibiotics and toxic compounds” function on Day 0, however an increase in antibiotic resistance genes after treatment with enrofloxacin was not observed. “Resistance to Fluoroquinolones” and “Erythromycin resistance”, of relevance given the study groups, were not statistically different in abundance between treatment groups. “Resistance to fluoroquinolones” increased during the study period regardless of treatment group. Despite small differences over the first weeks between treatment groups, at Day 112 the microbiota composition and functional profile was similar among all study groups. These findings show that metaphylaxis treatment of dairy calves with either enrofloxacin or tulathromycin have minimal impacts on the microbial composition and functional microbiota of dairy calves over time.
Lateral organ diversification in plants mediated by the ALOG protein family of transcription factors
Authors: Naramoto Satoshi , Jones Victor Arnold Shivas , Trozzi Nicola , Sato Mayuko , Toyooka Kiminori , Shimamura Masaki , Ishida Sakiko , Nishitani Kazuhiko , Ishizaki Kimitsune , Nishihama Ryuichi , Kohchi Takayuki , Dolan Liam , Kyozuka Junko
Published: July 2019

Land plant shoot structures evolved a diversity of lateral organs as morphological adaptations to the terrestrial environment, in which lateral organs independently evolved in each lineage in the sporophyte or gametophyte generation. The gametophyte meristem of the basally-diverging plant Marchantia polymorpha produces axes with non-photosynthetic scale-like lateral organs instead of leaves. Here we report that an ALOG (Arabidopsis LSH1 and Oryza G1) family protein in Marchantia, MpTAWAWA1 (MpTAW1), regulates meristem maintenance and lateral organ development. A mutation in MpTAW1, preferentially expressed in lateral organs, induces lateral organs with mis-specified identity and increased cell number, and furthermore, causes defects in apical meristem maintenance. Remarkably, MpTAW1 expression rescued the elongated-spikelet phenotype of a rice mutant of MpTAW1 homologue. This suggests that ALOG genes are co-opted to specify lateral organ identities in both gametophyte and sporophyte shoots by repressing lateral organ growth. We propose that the recruitment of ALOG-mediated lateral organ modification was in part responsible for the convergent evolution of independently-evolved lateral organs among highly divergent plant lineages and contributed to the morphological diversification of land plants.
Structure-function analysis of the Escherichia coli β–barrel assembly enhancing protease BepA suggests a role for a self-inhibitory state
Authors: Bryant Jack A. , Cadby Ian T. , Chong Zhi-Soon , Sevastsyanovich Yana R. , Morris Faye C. , Cunningham Adam F. , Kritikos George , Meek Richard W. , Banzhaf Manuel , Chng Shu-Sin , Henderson Ian R. , Lovering Andrew L.
Published: July 2019

The asymmetric Gram-negative outer membrane (OM) is the first line of defence for the bacteria against environmental insults and attack by antimicrobials. The key component of the OM barrier is the surface exposed lipopolysaccharide, which is transported to the surface by the essential lipopolysaccharide transport (Lpt) system. Correct folding of the Lpt system OM component, LptD, is essential and is regulated by a periplasmic metalloprotease, BepA. Here we present the crystal structure of BepA, solved to a resolution of 1.9 Å. Our structure comprises the zinc-bound m48 protease domain and a tetratricopeptide repeat (TPR) domain, consisting of four 2-helix TPR motifs and four non-TPR helices, leading to a nautilus-like shape in which the TPR repeats cup the protease domain. Using targeted mutagenesis approaches, we demonstrate that the protein is auto-regulated by the active-site plug. Further to this we reveal that mutation of a negative pocket, formed at the interface between the m48 and TPR domains, impairs BepA activity suggesting the pocket as a possible substrate binding site. We also identify a potential protein interaction site within the TPR cavity as being important for BepA function. Lastly, we provide evidence to show that increased antibiotic susceptibility in the absence of correctly functioning BepA occurs through disruption of OM lipid asymmetry, leading to reduced barrier function and increased cell permeability.
Epstein Barr virus genomes reveal population structure and type 1 association with endemic Burkitt lymphoma
Authors: Kaymaz Yasin , Oduor Cliff I. , Aydemir Ozkan , Luftig Micah A. , Otieno Juliana A. , Ong’echa John Michael , Bailey Jeffrey A. , Moormann Ann M.
Published: July 2019

Endemic Burkitt lymphoma (eBL), the most prevalent pediatric cancer in sub-Saharan Africa, is associated with malaria and Epstein Barr virus (EBV). In order to better understand the role of EBV in eBL, we improved viral DNA enrichment methods and generated a total of 98 new EBV genomes from both eBL cases (N=58) and healthy controls (N=40) residing in the same geographic region in Kenya. Comparing cases and controls, we found that EBV type 1 was significantly associated with eBL with 74.5% of patients (41/55) versus 47.5% of healthy children (19/40) carrying type 1 (OR=3.24, 95% CI=1.36 - 7.71,P=0.007). Controlling for EBV type, we also performed a genome-wide association study identifying 6 nonsynonymous variants in the genes EBNA1, EBNA2, BcLF1, and BARF1 that were enriched in eBL patients. Additionally, we observed that viruses isolated from plasma of eBL patients were identical to their tumor counterpart consistent with circulating viral DNA originating from the tumor. We also detected three intertypic recombinants carrying type 1 EBNA2 and type 2 EBNA3 regions as well as one novel genome with a 20 kb deletion resulting in the loss of multiple lytic and virion genes. Comparing EBV types, genes show differential variation rates as type 1 appears to be more divergent. Besides, type 2 demonstrates novel substructures. Overall, our findings address the complexities of EBV population structure and provide new insight into viral variation, which has the potential to influence eBL oncogenesis.

Key Points

EBV type 1 is more prevalent in eBL patients compared to the geographically matched healthy control group.

Genome-wide association analysis between cases and controls identifies 6 eBL-associated nonsynonymous variants in EBNA1, EBNA2, BcLF1, and BARF1 genes.

Analysis of population structure reveals that EBV type 2 exists as two genomic sub groups.
Host-microbiome coevolution promotes cooperation in a rock-paper-scissor dynamic
Authors: Lewin-Epstein Ohad , Hadany Lilach
Published: July 2019

Cooperation is a fundamental behavior observed in all forms of life. The evolution of cooperation has been widely studied, but almost all theories focused on the cooperating individual and its genes. We suggest a different approach, taking into account the microbes carried by the interacting individuals. Accumulating evidence reveal that microbes can affect their host wellbeing and behavior, yet hosts can evolve mechanisms to resist the manipulations of their microbes. We thus propose that coevolution of microbes with their hosts may favor microbes that induce their host to cooperate. Using computational modeling, we show that microbe-induced cooperation can evolve and be maintained in a wide range of conditions, including when facing hosts’ resistance to the microbial effect. We find that host-microbe coevolution leads the population to a rock-paper-scissors dynamic, that enables maintenance of cooperation in a polymorphic state. This theory may help explain occurrences of cooperation in a wide variety of organisms, including in cases that are difficult to explain by current theories. In addition, this study provides a new perspective on the coevolution of hosts and their microbiome, emphasizing the potential role of microbes in shaping their host behavior.