bluuebunny/crossref_metadata_2025 huggingface dataset:
FDG PET in Diffuse Spinal Carcinomatous Meningitis
Authors: Cuvilliers Cécile , Ahrweiller Flora , Vauléon Elodie , Castelli Joël , Palard-Novello Xavier
Published: April 2019

A 65-year-old man, diagnosed with right paranasal sinus neuroendocrine carcinoma with skull base invasion and ipsilateral lymph node involvement underwent chemotherapy. Six months later, the patient underwent radiation therapy for right cervical lymph node recurrence. Two months after the end of the radiation therapy, the patient was referred to our department to perform a whole-body FDG PET for therapeutic assessment. It showed diffuse intense FDG uptake of the whole spinal canal. The physical examination revealed walking disorders. Meningeal contrast enhancement on MRI of the brain and the spinal cord was leading to the diagnosis of carcinomatous meningitis.
Medical Improvisation Training as a Vehicle to Improve Empathetic Communication Skills in Nutrition and Dietetics Students
Authors: Thompson Kyle L. , Stetzler Sonja Kassis
Published: April 2019

Medical improvisation, based on the theater, is the adaptation of improvisational techniques to achieve medical objectives including empathetic patient-provider communication. Theatrical improvisations are unscripted dialogues among actors, intended to meet performance goals. In this pilot study, 2 consecutive cohorts of graduate-level dietetics students (N = 26) received 6 hours of medical improvisation training over their respective 9-month academic years. Pre- and postintervention questionnaires indicated statistically significant increases in students' perception scores regarding specific components of empathetic communication including collaboration, flexibility, and self-confidence. Medical improvisation training may be a promising avenue for developing communication skills among nutrition and dietetics students.
X-ray Raman scattering: a building block for nonlinear spectroscopy
Authors: Rohringer Nina
Published: April 2019

Ultraintense X-ray free-electron laser pulses of attosecond duration can enable new nonlinear X-ray spectroscopic techniques to observe coherent electronic motion. The simplest nonlinear X-ray spectroscopic concept is based on stimulated electronic X-ray Raman scattering. We present a snapshot of recent experimental achievements, paving the way towards the goal of realizing nonlinear X-ray spectroscopy. In particular, we review the first proof-of-principle experiments, demonstrating stimulated X-ray emission and scattering in atomic gases in the soft X-ray regime and first results of stimulated hard X-ray emission spectroscopy on transition metal complexes. We critically asses the challenges that have to be overcome for future successful implementation of nonlinear coherent X-ray Raman spectroscopy.

This article is part of the theme issue ‘Measurement of ultrafast electronic and structural dynamics with X-rays’.
Charge migration in photo-ionized aromatic amino acids
Authors: Trabattoni A. , Galli M. , Lara-Astiaso M. , Palacios A. , Greenwood J. , Tavernelli I. , Decleva P. , Nisoli M. , Martín F. , Calegari F.
Published: April 2019

Attosecond pump–probe spectroscopy is a unique tool for the direct observation of the light-activated electronic motion in molecules and it offers the possibility to capture the first instants of a chemical reaction. Recently, advances in attosecond technology allowed the charge migration processes to be revealed in biochemically relevant molecules. Although this purely electronic process might be key for a future chemistry at the electron time scale, the influence of this ultrafast charge flow on the reactivity of a molecule is still debated. In this work, we exploit extreme ultraviolet attosecond pulses to activate charge migration in two aromatic amino acids, namely phenylalanine and tryptophan. Advanced numerical calculations are performed to interpret the experimental data and to discuss the effects of the nuclear dynamics on the activated quantum coherences. By comparing the experimental results obtained in the two molecules, we show that the presence of different functional groups strongly affects the fragmentation pathways, as well as the charge rearrangement. The observed charge dynamics indeed present peculiar aspects, including characteristic periodicities and decoherence times. Numerical results indicate that, even for a very large molecule such as tryptophan, the quantum coherences can survive the nuclear dynamics for several femtoseconds. These results open new and important perspectives for a deeper understanding of the photo-induced charge dynamics, as a promising tool to control the reactivity of bio-relevant molecules via photo-excitation.

This article is part of the theme issue ‘Measurement of ultrafast electronic and structural dynamics with X-rays’.
Accuracy and precision of the RABBIT technique
Authors: Isinger M. , Busto D. , Mikaelsson S. , Zhong S. , Guo C. , Salières P. , Arnold C. L. , L'Huillier A. , Gisselbrecht M.
Published: April 2019

One of the most ubiquitous techniques within attosecond science is the so-called reconstruction of attosecond beating by interference of two-photon transitions (RABBIT). Originally proposed for the characterization of attosecond pulses, it has been successfully applied to the accurate determination of time delays in photoemission. Here, we examine in detail, using numerical simulations, the effect of the spatial and temporal properties of the light fields and of the experimental procedure on the accuracy of the method. This allows us to identify the necessary conditions to achieve the best temporal precision in RABBIT measurements.

This article is part of the theme issue ‘Measurement of ultrafast electronic and structural dynamics with X-rays’.
Measuring non-equilibrium dynamics in complex solids with ultrashort X-ray pulses
Authors: Buzzi Michele , Först Michael , Cavalleri Andrea
Published: April 2019

Strong interactions between electrons give rise to the complexity of quantum materials, which exhibit exotic functional properties and extreme susceptibility to external perturbations. A growing research trend involves the study of these materials away from equilibrium, especially in cases in which the stimulation with optical pulses can coherently enhance cooperative orders. Time-resolved X-ray probes are integral to this type of research, as they can be used to track atomic and electronic structures as they evolve on ultrafast timescales. Here, we review a series of recent experiments where femtosecond X-ray diffraction was used to measure dynamics of complex solids.

This article is part of the theme issue ‘Measurement of ultrafast electronic and structural dynamics with X-rays’.
Ultrafast dynamics of spin and orbital correlations in quantum materials: an energy- and momentum-resolved perspective
Authors: Cao Y. , Mazzone D. G. , Meyers D. , Hill J. P. , Liu X. , Wall S. , Dean M. P. M.
Published: April 2019

Many remarkable properties of quantum materials emerge from states with intricate coupling between the charge, spin and orbital degrees of freedom. Ultrafast photo-excitation of these materials holds great promise for understanding and controlling the properties of these states. Here, we introduce time-resolved resonant inelastic X-ray scattering (tr-RIXS) as a means of measuring the charge, spin and orbital excitations out of equilibrium. These excitations encode the correlations and interactions that determine the detailed properties of the states generated. After outlining the basic principles and instrumentations of tr-RIXS, we review our first observations of transient antiferromagnetic correlations in quasi two dimensions in a photo-excited Mott insulator and present possible future routes of this fast-developing technique. The increasing number of X-ray free electron laser facilities not only enables tackling long-standing fundamental scientific problems, but also promises to unleash novel inelastic X-ray scattering spectroscopies.

This article is part of the theme issue ‘Measurement of ultrafast electronic and structural dynamics with X-rays’.
Recent advances in ultrafast X-ray sources
Authors: Schoenlein Robert , Elsaesser Thomas , Holldack Karsten , Huang Zhirong , Kapteyn Henry , Murnane Margaret , Woerner Michael
Published: April 2019

Over more than a century, X-rays have transformed our understanding of the fundamental structure of matter and have been an indispensable tool for chemistry, physics, biology, materials science and related fields. Recent advances in ultrafast X-ray sources operating in the femtosecond to attosecond regimes have opened an important new frontier in X-ray science. These advances now enable: (i) sensitive probing of structural dynamics in matter on the fundamental timescales of atomic motion, (ii) element-specific probing of electronic structure and charge dynamics on fundamental timescales of electronic motion, and (iii) powerful new approaches for unravelling the coupling between electronic and atomic structural dynamics that underpin the properties and function of matter. Most notable is the recent realization of X-ray free-electron lasers (XFELs) with numerous new XFEL facilities in operation or under development worldwide. Advances in XFELs are complemented by advances in synchrotron-based and table-top laser-plasma X-ray sources now operating in the femtosecond regime, and laser-based high-order harmonic XUV sources operating in the attosecond regime.

This article is part of the theme issue ‘Measurement of ultrafast electronic and structural dynamics with X-rays’.
Development of ultrafast capabilities for X-ray free-electron lasers at the linac coherent light source
Authors: Coffee Ryan N. , Cryan James P. , Duris Joseph , Helml Wolfram , Li Siqi , Marinelli Agostino
Published: April 2019

The ability to produce ultrashort, high-brightness X-ray pulses is revolutionizing the field of ultrafast X-ray spectroscopy. Free-electron laser (FEL) facilities are driving this revolution, but unique aspects of the FEL process make the required characterization and use of the pulses challenging. In this paper, we describe a number of developments in the generation of ultrashort X-ray FEL pulses, and the concomitant progress in the experimental capabilities necessary for their characterization and use at the Linac Coherent Light Source. This includes the development of sub-femtosecond hard and soft X-ray pulses, along with ultrafast characterization techniques for these pulses. We also describe improved techniques for optical cross-correlation as needed to address the persistent challenge of external optical laser synchronization with these ultrashort X-ray pulses.

This article is part of the theme issue ‘Measurement of ultrafast electronic and structural dynamics with X-rays’.
Landscape drivers of genomic diversity and divergence in woodland Eucalyptus
Authors: Murray Kevin , Janes Jasmine , Bothwell Helen , Jones Ashley , Andrew Rose , Borevitz Justin
Published: April 2019

Spatial genetic patterns are influenced by numerous factors, and they can vary even among coexisting, closely related species due to differences in dispersal and selection. Eucalyptus (L’Héritier 1789; the “eucalypts”) are foundation tree species that provide essential habitat and modulate ecosystem services throughout Australia. Here we present a study of landscape genomic variation in two woodland eucalypt species, using whole genome sequencing of 388 individuals ofEucalyptus albensandEucalyptus sideroxylon. We found exceptionally high genetic diversity (π≈ 0.05) and low genome-wide, inter-specific differentiation (FST= 0.15). We found no support for strong, discrete population structure, but found substantial support for isolation by geographic distance (IBD) in both species. Using generalised dissimilarity modelling, we identified additional isolation by environment (IBE).Eucalyptus albensshowed moderate IBD, and environmental variables have a small but significant amount of additional predictive power (i.e., IBE).Eucalyptus sideroxylonshowed much stronger IBD, and moderate IBE. These results highlight the vast adaptive potential of these species, and set the stage for testing evolutionary hypotheses of interspecific adaptive differentiation across environments.
A Comparative Assessment of Visceral Leishmaniasis Burden in Two Eco-epidemiologically Different Countries, India and Sudan
Authors: Barley Kamal , Mubayi Anuj , Safan Muntaser , Castillo-Chavez Carlos
Published: April 2019

The two hyper–endemic regions for Visceral Leishmaniasis (VL) in the world are located in India and Sudan. These two countries account for more than half of the world’s VL burden. The regional risk factors associated with VL vary drastically per region. A mathematical model of VL transmission dynamics is introduced and parametrized to quantify risk of VL infection in India and Sudan via a careful analysis of VL prevalence level and the control reproductive number,, a metric often used to characterize the degree of endemicity. Parameters, associated with VL-epidemiology for India and Sudan, are estimated using data from health departmental reports, clinical trials, field studies, and surveys in order to assess potential differences between the hyper–endemic regions of India and Sudan. The estimated value of reproduction number for India is found to be 60% higher than that of Sudan (and). It is observed that theis most sensitive to the average biting rate and vector-human transmission rates irrespective of regional differences. The treatment rate is found to be the most sensitive parameter to VL prevalence in humans for both India and Sudan. Although the unexplained higher incidence of VL in India needs to be carefully monitored during long-term empirical follow-up, the risk factors associated with vectors are identified as more critical to dynamics of VL than factors related to humans through this modeling study.

Author Summary

The Visceral Leishmaniasis (VL) is a neglected tropical disease, primarily endemic in five countries, with India and Sudan having the highest burden. The risk factors associated with VL are either unknown in some regions or vary drastically among empirical studies. In this study, we collect VL-related data from multiple sources for the two different countries, India and Sudan, and use techniques from mathematical modeling to understand factors that may be critical in the spread and control of VL. The results suggest that the risk factors associated with disease progression are important in explaining high VL prevalence in both the countries. However, the likelihood of disease outbreak in India is much higher than that in Sudan and the probability of transmission between human and sandfly populations vary significantly between the two. The results have implications towards VL elimination and may require a review of current control priorities.
Relative performance of Oxford Nanopore MinION vs. Pacific Biosciences Sequel third-generation sequencing platforms in identification of agricultural and forest pathogens
Authors: Loit Kaire , Adamson Kalev , Bahram Mohammad , Puusepp Rasmus , Anslan Sten , Kiiker Riinu , Drenkhan Rein , Tedersoo Leho
Published: April 2019

Culture-based molecular characterization methods have revolutionized detection of pathogens, yet these methods are either slow or imprecise. The second-generation sequencing tools have much improved precision and sensitivity of detection, but the analysis processes are costly and take several days. Of third-generation techniques, the portable Oxford Nanopore MinION device has received much attention because of its small size and possibility of rapid analysis at reasonable cost. Here, we compare the relative performance of two third-generation sequencing instruments, MinION and Pacific Biosciences Sequel in identification and diagnostics of pathogens from conifer needles and potato leaves and tubers. We demonstrate that Sequel is efficient in metabarcoding of complex samples, whereas MinION is not suited for this purpose due to the high error rate and multiple biases. However, we find that MinION can be utilized for rapid and accurate identification of dominant pathogenic organisms from plant tissues following both amplicon-based and metagenomics-based approaches. Using the PCR-free approach with shortened extraction and incubation times, we performed the entire MinION workflow from sample preparation through DNA extraction, sequencing, bioinformatics and interpretation in two and half hours. We advocate the use of MinION for rapid diagnostics of pathogens, but care needs to be taken to control or account for all potential technical biases.

IMPORTANCE

We develop new and rapid protocols for MinION-based third-generation diagnostics of plant pathogens that greatly improves the speed and precision of diagnostics. Due to high error rate and technical biases in MinION, PacBio Sequel platform is more useful for amplicon-based metabarcoding from complex biological samples.
Unusual metabolism and hypervariation in the genome of a Gracilibacteria (BD1-5) from an oil degrading community
Authors: Sieber Christian M.K. , Paul Blair G. , Castelle Cindy J. , Hu Ping , Tringe Susannah G. , Valentine David L. , Andersen Gary L. , Banfield Jillian F.
Published: April 2019

The Candidate Phyla Radiation (CPR) comprises a large monophyletic group of bacterial lineages known almost exclusively based on genomes obtained using cultivation-independent methods. Within the CPR, Gracilibacteria (BD1-5) are particularly poorly understood due to undersampling and the inherent fragmented nature of available genomes. Here, we report the first closed, curated genome of a Gracilibacteria from an enrichment experiment inoculated from the Gulf of Mexico and designed to investigate hydrocarbon degradation. The gracilibacterium rose in abundance after the community switched to dominance byColwellia. Notably, we predict that this gracilibacterium completely lacks glycolysis, the pentose phosphate and Entner-Doudoroff pathways. It appears to acquire pyruvate, acetyl-CoA and oxaloacetate via degradation of externally derived citrate, malate and amino acids and may use compound interconversion and oxidoreductases to generate and recycle reductive power. The initial genome assembly was fragmented in an unusual gene that is hypervariable within a repeat region. Such extreme local variation is rare, but characteristic of genes that confer traits under pressure to diversify within a population. Notably, the four major repeated 9-mer nucleotide sequences all generate a proline-threonine-aspartic acid (PTD) repeat. The genome of an abundantColwellia psychrerythraeapopulation has a large extracellular protein that also contains the repeated PTD motif. Although we do not know the host for the BD1-5 cell, the high relative abundance of theC. psychrerythraeapopulation and the shared surface protein repeat may indicate an association between these bacteria.

Importance

CPR bacteria are generally predicted to be symbionts due to their extensive biosynthetic deficits. Although monophyletic, they are not monolithic in terms of their lifestyles. The organism described here appears to have evolved an unusual metabolic platform not reliant on glucose or pentose sugars. Its biology appears to be centered around bacterial host-derived compounds and/or cell detritus. Amino acids likely provide building blocks for nucleic acids, peptidoglycan and protein synthesis. We resolved an unusual repeat region that would be invisible without genome curation. The nucleotide sequence is apparently under strong diversifying selection but the amino acid sequence is under stabilizing selection. The amino acid repeat also occurs in a surface protein of a coexisting bacterium, suggesting co-location and possibly interdependence.
Three-phase transitions to reproductive isolation: The roles of utilization mismatch and residual selection
Authors: Meszéna Géza , Dieckmann Ulf
Published: April 2019

The adaptive emergence of reproductive isolation is increasingly recognized as a key mechanism of sympatric speciation. Here we aim at establishing a deeper understanding of the complex multilocus dynamics underlying such speciation transitions under resource competition. In reality, a single population’s resource utilization can never exactly match a resource distribution, making residual selection pressures inevitable. We find that this commonly leads to three-phase transitions to reproductive isolation. First, partial assortativity emerges, quickly adjusting a population’s variance to the resource distribution’s variance. Second, allelic variance slowly erodes across loci, allowing an increasingly bimodal phenotype distribution to emerge. Third, a fast transition occurs toward full bimodality in conjunction with practically complete reproductive isolation of the emerging two species. The first phase is driven by frequency-dependent divergent ecological selection. The second phase is driven by self-accelerating residual ecological selection: the more loci code for the selected phenotype, the slower is this intermediate phase. The third phase is driven by self-accelerating sexual selection. We study three types of mismatch-driven speciation, resulting from (i) incongruences between the shapes of resource distributions and competition kernels, (ii) low numbers of loci, and (iii) premature cessations of the first phase’s variance expansion. Our results suggest that the incomplete separation of incipient species, a characteristic of the second phase, is common in nature, which is likely resulting in detectable genetic footprints of three-phase transitions to reproductive isolation occurring in nature.
Cytoskeleton members, MVBs and the ESCRT-III HvSNF7s are putative key players for protein sorting into protein bodies during barley endosperm development
Authors: Roustan Valentin , Hilscher Julia , Weidinger Marieluise , Reipert Siegfried , Shabrangy Azita , Gebert Claudia , Dietrich Bianca , Dermendjiev Georgi , Roustan Pierre-Jean , Stoger Eva , Ibl Verena
Published: April 2019

Cereal endosperm is a short-lived tissue adapted for nutrient storage, containing specialized organelles, such as protein bodies (PBs) and protein storage vacuoles (PSVs), for the accumulation of storage proteins. PBs can be used as efficient biotechnological systems to produce high yields of stable recombinant proteins. During development, protein trafficking and storage require an extensive reorganization of the endomembrane system. Consequently, endomembrane-modifying proteins will influence the final grain quality, yield and recombinant protein production. Barley, a cereal crop of worldwide importance for the brewing industry, animal feed and to a lesser extent, human nutrition, has been identified as promising candidate for recombinant protein production. However, little is known about the molecular mechanism underlying endomembrane system remodeling during barley grain development. By usingin vivolabel-free quantitative proteomics profiling, we quantified 1,822 proteins across developing barley grains. Based on proteome annotation and a homology search, 95 proteins associated with the endomembrane system were identified, and 83 of these exhibited significant changes in abundance during grain development. Clustering analysis allowed characterization of three different development stages; notably, integration of proteomics data within situsubcellular microscopic analyses showed a high abundance of cytoskeleton proteins associated with acidified protein bodies at the early development stages. Endosomal sorting complex required for transport (ESCRT)-related proteins and their transcripts are most abundant at early and mid-development. Specifically, multivesicular bodies (MVBs), and the ESCRT-III HvSNF7 proteins are associated with protein bodies (PBs) during barley endosperm development. Taken together, our proteomics results specifically identified members of the cytoskeleton, MVBs, and ESCRT as putative key players for protein sorting into PBs during barley endosperm development. These results present a comprehensive overview of proteins involved in the rearrangement of the endomembrane system during barley early grain development and will provide the basis for future work on engineering the endomembrane system to optimize nutrient content and to produce high yields of recombinant proteins.
Biomolecular Contrast Agents for Optical Coherence Tomography
Authors: Lu George J. , Chou Li-dek , Malounda Dina , Patel Amit K. , Welsbie Derek S. , Chao Daniel L. , Ramalingam Tirunelveli , Shapiro Mikhail G.
Published: April 2019

Optical coherence tomography (OCT) has gained wide adoption in biological and medical imaging due to its exceptional tissue penetration, 3D imaging speed and rich contrast. However, OCT plays a relatively small role in molecular and cellular imaging due to the lack of suitable biomolecular contrast agents. In particular, while the green fluorescent protein has provided revolutionary capabilities to fluorescence microscopy by connecting it to cellular functions such as gene expression, no equivalent reporter gene is currently available for OCT. Here we introduce gas vesicles, a unique class of naturally evolved gas-filled protein nanostructures, as the first genetically encodable OCT contrast agents. The differential refractive index of their gas compartments relative to surrounding aqueous tissue and their nanoscale motion enables gas vesicles to be detected by static and dynamic OCT at picomolar concentrations. Furthermore, the OCT contrast of gas vesicles can be selectively erasedin situwith ultrasound, allowing unambiguous assignment of their location. In addition, gas vesicle clustering modulates their temporal signal, enabling the design of dynamic biosensors. We demonstrate the use of gas vesicles as reporter genes in bacterial colonies and as purified contrast agentsin vivoin the mouse retina. Our results expand the utility of OCT as a unique photonic modality to image a wider variety of cellular and molecular processes.
Does Antibody Stabilize the Ligand Binding in GP120 of HIV-1 Envelope Protein? Evidence from MD Simulation
Authors: Pandey Vishnudatt , Tiwari Rakesh Kumar , Ojha Rajendra Prasad , Dubey Kshatresh Dutta
Published: April 2019

CD4-mimetic HIV-1 entry inhibitors are small sized molecules which imitate similar conformational flexibility in gp120 as CD4 receptor, the mechanism of the conformational flexibility instigated by these small sized inhibitors, however, is little known. Likewise, the effect of the antibody on the function of these inhibitors is also less studied. In this study, we present a thorough inspection of the mechanism of the conformational flexibility induced by a CD4-mimetic inhibitor, NBD-557, using Molecular Dynamics Simulations and free energy calculations. Our result shows a functional importance of Asn239 in substrate instigated conformational dynamics in gp120. The MD simulations of Asn239Gly mutant provide a less dynamic gp120 in the presence of NBD-557 without incapacitating the binding enthalpy of NBD-557. The MD simulations of complex with the antibody clearly shows the enhanced affinity of NBD-557 due to the presence of the antibody which is in good agreement with experimental Isothermal Titration Calorimetry results (Biochemistry2006,45, 10973-10980).
The transcription factor Zt107320 affects the dimorphic switch, growth and virulence of the fungal wheat pathogenZymoseptoria tritici
Authors: Habig Michael , Bahena-Garrido Sharon Marie , Barkmann Friederike , Haueisen Janine , Stukenbrock Eva Holtgrewe
Published: April 2019

Zymoseptoria triticiis a filamentous fungus causing Septoria tritici blotch in wheat. The pathogen has a narrow host range and infections of grasses other than susceptible wheat are blocked early after stomatal penetration. During these abortive infections the fungus shows a markedly different expression pattern. However, the underlying mechanisms causing differential gene expression during host and non-host interaction are largely unknown, but likely include transcriptional regulators responsible for the onset of an infection program in compatible hosts. In the rice blast pathogenMagnaporthe oryzae, MoCOD1, a member of the fungal Zn(II)2Cys6transcription factor family, has been shown to directly affect pathogenicity. Here, we analyse the role of the putative transcription factor Zt107320, a homolog of MoCOD1, during infection of compatible and incompatible hosts byZ. tritici. We show for the first time thatZt107320is differentially expressed in host versus non-host infections and that lower expression corresponds to an incompatible infection of non-hosts. Applying reverse genetics approaches we further show that Zt107320 regulates the dimorphic switch as well as the growth rate ofZ. triticiand affects fungal cell wall compositionin vitro. Moreover, ΔZt107320mutants showed reduced virulence during compatible infections of wheat. We conclude that Zt107320 directly influences pathogen fitness and propose that Zt107320 regulates growth processes and pathogenicity during infection. Our results suggest that this putative transcription factor is involved in discriminating compatible and non-compatible infections.
A novel approach to localize cortical TMS effects
Authors: Weise Konstantin , Numssen Ole , Thielscher Axel , Hartwigsen Gesa , Knösche Thomas R.
Published: April 2019

Despite the widespread use of transcranial magnetic stimulation (TMS), the precise cortical location underlying the physiological and behavioral stimulation effects are still only coarsely known. So far, mapping strategies rely on center of gravity approaches and therefore localize the stimulated cortical site only approximately and indirectly. Focusing on the motor cortex, we present a novel method to reliably determine the effectively stimulated cortical site at the individual subject level. The approach combines measurements of motor evoked potentials (MEPs) at different coil positions and orientations with numerical modeling of induced electric fields. We identify sharply bounded cortical areas around the gyral crowns and rims of the motor hand area as the origin of MEPs and show that the tangential component and the magnitude of the electric field is most relevant for the observed effect. To validate our approach, we determined motor thresholds for coil positions and orientations for the predicted cortical target. Our methods allows for the identification of optimal coil positions and orientations. Moreover, we used extensive uncertainty and sensitivity analyses to verify the robustness of the method and identify the most critical model parameters. Our generic approach improves the localization of the cortex area stimulated by TMS and may be transferred to other modalities such as language mapping.
Strong spatial genetic structure in a Baltic Sea herbivore due to recent range expansion, multiple bottlenecks and low connectivity
Authors: De Wit Pierre , Jonsson Per R. , Pereyra Ricardo T. , Panova Marina , André Carl , Johannesson Kerstin
Published: April 2019

In the Baltic Sea, recent range expansions following the opening of the Danish straits have resulted in a low-diversity ecosystem, both among and within species. However, relatively little is known about population genetic patterns within the basin, except for in a few commercially caught species and some primary producers thought to be ecosystem engineers. Here, we investigate the population genetic structure of the ecologically important crustaceanIdotea balthicathroughout the Baltic Sea using an array of 33,774 genome-wide SNP markers derived from 2b-RAD sequencing. We also generate a biophysical connectivity matrix, with which we compare the genomic data. We find strong population structure on small scales across the Baltic Sea, and that genomic patterns in most cases closely match biophysical connectivity, suggesting that current patterns are important for dispersal of this species. We also find a strong signal of multiple bottlenecks during the initial range expansion, in the form of reduced heterozygosity along the historical expansion front. The lack of gene flow among sampling sites in the Baltic Sea environmental gradient potentiates local adaptation, while at the same time also increasing genetic drift in low-diversity areas.
Ataxin-3 links NOD2 and TLR2 mediated innate immune sensing and metabolism in myeloid cells
Authors: Chapman Thomas , Corridoni Daniele , Shiraishi Seiji , Pandey Sumeet , Aulicino Anna , Wigfield Simon , do Carmo Costa Maria , Thézénas Marie-Laëtitia , Paulson Henry , Fischer Roman , Kessler Benedikt M , Simmons Alison
Published: April 2019

The interplay between NOD2 and TLR2 following recognition of components of the bacterial cell wall peptidoglycan is well established, however their role in redirecting metabolic pathways in myeloid cells to degrade pathogens and mount antigen presentation remains unclear. We show NOD2 and TLR2 mediate phosphorylation of the deubiquitinase ataxin-3 via RIPK2 and TBK1. In myeloid cells ataxin-3 associates with the mitochondrial cristae protein MIC60, and is required for oxidative phosphorylation. Depletion of ataxin-3 leads to impaired induction of mitochondrial reactive oxygen species (mROS) and defective bacterial killing. A mass spectrometry analysis of NOD2/TLR2 triggered ataxin-3 deubiquitination targets revealed immunometabolic regulators, including HIF-1α and LAMTOR1 that may contribute to these effects. Thus, we define how ataxin-3 plays an essential role in NOD2 and TLR2 sensing and effector functions in myeloid cells.

Significance Statement

In recent years it has become clear that cross-talk between metabolic and immune pathways is central to the regulation of host defence. This interplay appears of particular importance in myeloid cells including dendritic cells and macrophages, but it is unclear how two of their key bacterial sensors NOD2 and TLR2 influence metabolism. Here, we define how NOD2/TLR2 signal in myeloid cells to drive optimal mitochondrial functioning required for bacterial destruction. We uncover a new role for Ataxin-3, a deubiquitinase required for non-selective autophagy, in this pathway. We provide a non-biased analysis of Ataxin-3 targets generating evidence for a role in deubiquitination of metabolic mediators during myeloid cell differentiation that will provide an important basis for further study.
Tomato Prf requires NLR helpers NRC2 and NRC3 to confer resistance against the bacterial speck pathogen Pseudomonas syringae pv. tomato
Authors: Wu Chih-Hang , Kamoun Sophien
Published: April 2019

Bacterial speck, caused by the pathogen Pseudomonas syringae pv. tomato, is one of the most common diseases in tomato production. Together with Pto kinase, the NLR (nucleotide-binding domain leucine-rich repeat containing) protein Prf confers resistance against the bacterial speck pathogen by recognizing AvrPto and AvrPtoB, two Type III effector proteins secreted by P. syringae pv. tomato. This Prf/Pto pathway is part of a complex NLR network in solanaceous plants that mediates resistance to diverse pathogens through the helper NLR proteins NRCs (NLR required for cell death). We previously showed that, in Nicotiana benthamiana, the hypersensitive cell death elicited by expression of AvrPto and Pto, which activate immunity through the endogenous Prf ortholog NbPrf, requires functionally redundant NRC2 and NRC3. However, whether tomato (Solanum lycopersicum) Prf (SlPrf) confers resistance to the bacterial speck pathogen through NRC2 and NRC3 has not been determined. In this study, we show that SlPrf requires NRC2 and NRC3 to trigger hypersensitive cell death and disease resistance in both N. benthamiana and tomato. We found that the hypersensitive cell death induced by AvrPtoB/Pto/SlPrf in N. benthamiana is compromised when NRC2 and NRC3 are silenced, indicating that SlPrf is an NRC2/3-dependent NLR. We validated this finding by showing that silencing NRC2 and NRC3 in the bacterial speck resistant tomato ‘Rio Grande 76R’ compromised Prf-mediated resistance. These results indicate that the NRC network extends beyond N. benthamiana to solanaceous crops.
CRISPR-SID: identifying EZH2 as a druggable target for desmoid tumors viain vivodependency mapping
Authors: Naert Thomas , Tulkens Dieter , Van Nieuwenhuysen Tom , Przybyl Joanna , Demuynck Suzan , van de Rijn Matt , Al Jazrawe Mushriq , Alman Benjamin , Coucke Paul J. , De Leeneer Kim , Vanhove Christian , Savvides Savvas N. , Creytens David , Vleminckx Kris
Published: April 2019

Cancer precision medicine implies identification of tumor-specific vulnerabilities associated with defined oncogenic pathways. Desmoid tumors are soft-tissue neoplasms strictly driven by Wnt signaling network hyperactivation. Despite this clearly defined genetic etiology and the strict and unique implication of the Wnt/β-catenin pathway, no specific molecular targets for these tumors have been identified. To address this caveat, we developed fast and semi-high throughput geneticXenopus tropicalisdesmoid tumor models to identify and characterize novel drug targets. We used multiplexed CRISPR/Cas9 genome editing in these models to simultaneously target a tumor suppressor gene (apc) and candidate dependency genes. Our methodology CRISPR/Cas9 Selection mediated Identification of Dependencies (CRISPR-SID) uses calculated deviations between experimentally observed gene editing outcomes and deep-learning-predicted double strand break repair patterns, to identify genes under negative selection during tumorigenesis. This revealedEZH2andSUZ12, both encoding polycomb repressive complex 2 components, and the transcription factorCREB3L1, as genetic dependencies for desmoid tumors.In vivoEZH2 inhibition by Tazemetostat induced partial regression of established autochthonous tumors.In vitromodels of patient desmoid tumor cells revealed a direct effect of Tazemetostat on Wnt pathway activity. CRISPR-SID represents a potent novel approach forin vivomapping of tumor vulnerabilities and drug target identification.

Significance Statement

CRISPR-SID was established in the diploid frogXenopus tropicalisforin vivoelucidation of cancer cell vulnerabilities. CRISPR-SID uses deep learning predictions and binomial theory to identify genes under positive or negative selection during autochthonous tumor development. Using CRISPR-SID in a genetic model for desmoid tumors, treatment-recalcitrant mesenchymal tumors driven by hyper-activation of the Wnt signaling pathway, we identifiedEZH2andSUZ12, both encoding critical components of the polycomb repressive complex 2, as dependency genes for desmoid. Finally, we demonstrate the promise of EZH2 inhibition as a novel therapeutic strategy for desmoid tumors. With the simplicity of CRISPR sgRNA multiplexing inXenopusembryos the CRISPR-SID method may be applicable to reveal vulnerabilities in other tumor types.
History of rare diseases and their genetic causes - a data driven approach
Authors: Ehrhart Friederike , Willighagen Egon L. , Kutmon Martina , Hoften Max van , Sangani Nasim Bahram , Curfs Leopold G.M. , Evelo Chris T.
Published: April 2019

This dataset provides information about monogenic, rare diseases with a known genetic cause supplemented with manually extracted provenance of both the disease and the discovery of the underlying genetic cause of the disease.

We collected 4166 rare monogenic diseases according to their OMIM identifier, linked them to 3163 causative genes which are annotated with Ensembl identifiers and HGNC symbols. The PubMed identifier of the scientific publication, which for the first time describes the rare disease, and the publication which found the gene causing this disease were added using information from OMIM, Wikipedia, Google Scholar, Whonamedit, and PubMed. The data is available as a spreadsheet and as RDF in a semantic model modified from DisGeNET.

This dataset relies on publicly available data and publications with a PubMed IDs but this is to our knowledge the first time this data has been linked and made available for further study under a liberal license. Analysis of this data reveals the timeline of rare disease and causative genes discovery and links them to developments in methods and databases.
Larvicidal evaluation of the Origanum majorana L. Essential Oil against the larvae of the Aedes aegypti mosquito
Authors: Chaves Renata do Socorro Barbosa , Martins Rosany Lopes , Rodrigues Alex Bruno Lobato , Rabelo Érica de Menezes , Farias Ana Luzia Ferreira , Araújo Camila Mendes da Conceição Vieira , Sobral Talita Fernandes , Galardo Allan Kardec Ribeiro , de Almeida Sheylla Susan Moreira da Silva
Published: April 2019

This study evaluated the larvicidal activity of O. majorana essential oil, identified the chemical composition, evaluated the antimicrobial, cytotoxic and antioxidant potential. The larvicidal activity was evaluated against larvae of the third stage of Aedes aegypti, whereas the chemical composition was identified by gas chromatography coupled to mass spectrometer, the antimicrobial activity was carried out against the bacteria Pseudomonas aeruginosa, Escherichia coli and Staphylococcus auereus, the antioxidant activity was evaluated from of 2.2-diphenyl-1-picryl-hydrazila sequestration and Artemia salina cytotoxicity. Regarding to the results, the larvicidal activity showed that O. majorana essential oil caused high mortality in A. aegypti larvae. In the chromatographic analysis, the main component found in O. majorana essential oil was pulegone (57.05%), followed by the other components verbenone (16.92%), trans-p-menthan-2-one (8.57%), iso-menthone (5.58%), piperitone (2.83%), 3-octanol (2.35%) and isopulegol (1.47%). The antimicrobial activity showed that E. coli and P. aeruginosa bacteria were more sensitive to oil than S. aureus, which was resistant at all concentrations. Essential oil did not present antioxidant activity, but it has high cytotoxic activity against A. salina.
The human microbiota is associated with cardiometabolic risk across the epidemiologic transition
Authors: Fei Na , Bernabé Beatriz Peñalver , Lie Louise , Baghdan Danny , Bedu-Addo Kweku , Plange-Rhule Jacob , Forrester Terrence E. , Lambert Estelle V. , Bovet Pascal , Gottel Neil , Riesen Walter , Korte Wolfgang , Luke Amy , Kliethermes Stephanie A. , Layden Brian T. , Gilbert Jack A. , Dugas Lara R.
Published: April 2019

Oral and fecal microbial biomarkers have previously been associated with cardiometabolic (CM) risk, however, no comprehensive attempt has been made to explore this association in minority populations or across different geographic regions. We characterized gut- and oral-associated microbiota and CM risk in 655 participants of African-origin, aged 25-45, from Ghana, South Africa, Jamaica, and the United States (US). CM risk was classified using the CM risk cut-points for elevated waist circumference, elevated blood pressure and elevated fasted blood glucose, low high-density lipoprotein (HDL), and elevated triglycerides. Gut-associated bacterial alpha diversity negatively correlated with elevated blood pressure and elevated fasted blood glucose. Similarly, gut bacterial beta diversity was also significantly differentiated by waist circumference, blood pressure, triglyceridemia and HDL-cholesterolemia. Notably, differences in inter- and intra-personal gut microbial diversity were geographic-region specific. Participants meeting the cut-points for 3 out of the 5 CM risk factors were significantly more enriched with Lachnospiraceae, and were significantly depleted of Clostridiaceae, Peptostreptococcaceae, andPrevotella. The predicted relative proportions of the genes involved in the pathways for lipopolysaccharides (LPS) and butyrate synthesis were also significantly differentiated by the CM risk phenotype, whereby genes involved in the butyrate synthesis via lysine, glutarate and 4-aminobutyrate/succinate pathways and LPS synthesis pathway were enriched in participants with greater CM risk. Furthermore, inter-individual oral microbiota diversity was also significantly associated with the CM risk factors, and oral-associatedStreptococcus, Prevotella, andVeillonellawere enriched in participants with 3 out of the 5 CM risk factors. We demonstrate that in a diverse cohort of African-origin adults, CM risk is significantly associated with reduced microbial diversity, and the enrichment of specific bacterial taxa and predicted functional traits in both gut and oral environments. As well as providing new insights into the associations between the gut and oral microbiota and CM risk, this study also highlights the potential for novel therapeutic discoveries which target the oral and gut microbiota in CM risk.
Targeting the dysfunctional mitochondrial respiration in drug resistant B-cell acute lymphoblastic leukemia
Authors: Nair Rajesh R. , Piktel Debbie , Thomas Patrick , Hathaway Quincy A. , Rellick Stephanie L. , Saralkar Pushkar , Martin Karen H. , Geldenhuys Werner J. , Hollander John M. , Gibson Laura F.
Published: April 2019

Reprogramming of cellular pathways is a crucial mechanism of drug resistance and survival in refractory acute lymphoblastic leukemia (ALL) cells. In the present study, we performed an unbiased gene expression analysis and identified a dysfunctional mitochondrial respiration program in drug-resistant ALL cells grown in a co-culture system with bone marrow stromal cells (BMSC). Specifically, the activity of the complexes within the electron transport chain was significantly downregulated, correlated with decreased mitochondrial mass and ATP production in drug-resistant ALL cells. To validate mitochondrial respiration as a druggable target, we utilized pyrvinium pamoate (PP), a known inhibitor of mitochondrial respiration and documented its anti-leukemic activity in several ALL cell lines grown alone or in co-culture with BMSC. To increase the bioavailability profile of PP, we successfully encapsulated PP in a nanoparticle drug delivery system and demonstrated that it retained its anti-leukemic activity in a hemosphere assay. PP anti-leukemic activity was decreased by the addition of sodium pyruvate, and furthermore, PP was found to have an additive anti-leukemic effect when used in combination with rotenone, a mitochondrial complex I inhibitor with activity similar to PP on the mitochondrial respiration. Importantly, PP’s cell death activity was found to be specific for leukemic cells as primary normal immune cells were resistant to PP-mediated cell death. In conclusion, we have demonstrated that PP is a novel therapeutic lead compound that counteracts the respiratory reprogramming found in refractory ALL cells.
Conspecifics, not plant reproductive tissues, reduce omnivore prey consumption
Authors: Rinehart S. , Long J.D.
Published: April 2019

Plant reproductive tissues (PRTs) can decrease (via reduced consumption) or increase (via numerical response) an omnivores consumption of animal prey. Although PRTs can increase predation pressure through numerical responses of omnivores, PRTs may also suppress predation by increasing omnivore interactions with conspecifics. Despite this potential, studies of the impacts of PRTs on predation by omnivores often overlook the effect of these tissues on intraspecific interactions between omnivores. We designed three studies to examine how PRTs and conspecific density impact prey consumption by ladybeetle omnivores. First, we assessed how PRTs impact scale insect consumption by isolated ladybeetles. Second, we measured how PRTs influence ladybeetle prey suppression when numerical responses were possible. Third, because initial experiments suggested the consumption rates of individual ladybeetles depended upon conspecific density, we compared per capita consumption rates of ladybeetles across ladybeetle density. PRTs did not influence prey consumption by isolated ladybeetles. When numerical responses were possible, PRTs did not influence total predation on prey despite increasing ladybeetle density, suggesting that PRTs decreased per capita prey consumption by ladybeetles. The discrepancy between our lab and field studies is likely a consequence of differences in ladybeetle density - the presence of only two other conspecifics decreased per capita prey consumption by 76%. Our findings suggest that PRTs may not alter the population level effects of omnivores on prey when omnivore numerical responses are offset by reductions in per capita predation rate.