bluuebunny/crossref_metadata_2025 huggingface dataset:
Nebula: Ultra-efficient mapping-free structural variant genotyper
Authors: Khorsand Parsoa , Hormozdiari Fereydoun
Published: March 2019

Motivation

Large scale catalogs of common genetic variants (including indels and structural variants) are being created using data from second and third generation whole-genome sequencing technologies. However, the genotyping of these variants in newly sequenced samples is a nontrivial task that requires extensive computational resources. Furthermore, current approaches are mostly limited to only specific types of variants and are generally prone to various errors and ambiguities when genotyping events in repeat regions. Thus we are proposing an ultra-efficient approach for genotyping any type of structural variation that is not limited by the shortcomings and complexities of current mapping-based approaches.

Results

Our method Nebula utilizes the changes in the count of k-mers to predict the genotype of common structural variations. We have shown that not only Nebula is an order of magnitude faster than mapping based approaches for genotyping deletions and mobile-element insertions, but also has comparable accuracy to state-of-the-art approaches. Furthermore, Nebula is a generic framework not limited to any specific type of event.

Availability

Nebula is publicly available at https://github.com/Parsoa/NebulousSerendipity
Chromatin arranges in chains of mesoscale domains with nanoscale functional topography independent of cohesin
Authors: Miron Ezequiel , Oldenkamp Roel , Brown Jill M. , Pinto David M. S. , Xu C. Shan , Faria Ana R. , Shaban Haitham A. , Rhodes James D. P. , Innocent Cassandravictoria , de Ornellas Sara , Hess Harald F. , Buckle Veronica , Schermelleh Lothar
Published: March 2019

Three-dimensional (3D) chromatin organization plays a key role in regulating mammalian genome function, however many of its physical features at the single-cell level remain underexplored. Here we use 3D super-resolution and scanning electron microscopy to analyze structural and functional nuclear organization in somatic cells. We identify linked chromatin domains (CDs) composed of irregular ∼200-300-nm-wide aggregates of nucleosomes that can overlap with individual topologically associating domains and are distinct from a surrounding RNA-populated interchromatin region. High-content mapping uncovers confinement of cohesin and active histone modifications to surfaces and enrichment of repressive modifications towards the core of CDs in both hetero- and euchromatic regions. This nanoscale functional topography is temporarily relaxed in post-replicative chromatin, but remarkably persists after ablation of cohesin. Our findings establish CDs as physical and functional modules of mesoscale genome organization.
Inter-Individual and Inter-Strain Differences in Cognitive and Social Abilities of Dark Agouti and Wistar Han Rats
Authors: Alonso Lucille , Peeva Polina , Ramos-Prats Arnau , Alenina Natalia , Winter York , Rivalan Marion
Published: March 2019

Background

Healthy animals showing extreme behaviours spontaneously that resemble human psychiatric symptoms are relevant models to study the natural psychobiological processes of maladapted behaviours. Healthy poor decision makers (PDMs) identified using a Rat Gambling Task, co-express a combination of cognitive and reward-based characteristics similar to symptoms observed in human patients with impulse-control disorders. The main goals of this study were to 1) confirm the existence of PDMs and their unique behavioural phenotypes in the Dark Agouti (DA) and Wistar Han (WH), 2) to extend the behavioural profile of the PDMs to probability-based decision-making and social behaviours and 3) to discuss how the key traits of each strain could be relevant for biomedical research.

Methods

We compared cognitive abilities, natural behaviours and physiological responses in DA and WH rats using several tests. We analysed the results at the strain and the individual level.

Results

Previous findings in WH rats were reproduced and could be generalized to DA. Each PDM of either strain displayed a similar, naturally occurring, combination of behavioural traits, including possibly higher social rank, but no deficits in probability-based decision-making. A Random forest analysis revealed interesting discriminating traits between WH and DA.

Conclusion

The reproducibility and conservation of the socio-cognitive and behavioural phenotypes of GDM (good decision maker) and PDM individuals in the two genetically different strains of WH and DA support a good translational validity of these phenotypes. Both DA and WH rat strains present large phenotypic variations in behaviour pertinent for the study of the underlying mechanisms of poor decision making and associated disorders.
Pan-viral protection against arboviruses by targeting inoculation site-based skin macrophages
Authors: Bryden Steven R , Pingen Marieke , Lefteri Daniella A , Major Jack , Delang Leen , Jacobs Sofie , Abdelnabi Rana , Neyts Johan , Miltenburg Janne , Khalid Henna , Tuplin Andrew , Merits Andres , Pondeville Emilie , Edgar Julia , Graham Gerard J , Shams Kave , McKimmie Clive S
Published: March 2019

Arthropod-borne viruses (arboviruses) are important human pathogens for which there are no specific antiviral medicines. The large number of genetically-distinct arbovirus species, coupled with the unpredictable nature of their outbreaks, has made developing virus-specific anti-viral medicines challenging. Instead, we have defined and targeted a key aspect of the host innate immune response to virus at the arthropod bite that is common to all arbovirus infections, potentially circumventing the need for virus-specific therapies at this site. Using mouse models and human skin explants, we identify innate immune responses by dermal macrophages in the skin as a key determinant of disease severity. Post-exposure treatment of the inoculation site by a topical innate immune agonist significantly suppressed both the local and subsequent systemic course of infection and improved clinical outcome in mice to infection with a variety of arboviruses from the Alphavirus, Flavivirus and Orthobunyavirus genuses. In the absence of treatment, anti-viral interferon expression to virus in the skin was restricted to dermal dendritic cells. In contrast, targeting the more populous skin-resident macrophages with an immune agonist elicited protective responses in key cellular targets of virus that otherwise replicated virus to high levels. By defining and targeting a key aspect of the innate immune response to virus at the mosquito bite site, we have shown that it is possible to improve outcome to infection by targeting pathways activated at the site of inoculation, and thereby identified a putative new strategy for limiting disease following infection with a variety of genetically-distinct arboviruses.

One-sentence summary

We demonstrate that activation of innate immune responses to arbovirus at the mosquito bite is a limiting factor for preventing efficient systemic dissemination of virus and that therapeutic targeting of skin-resident macrophages can have defining inhibitory effects on the later systemic course.
Subtle, Seasonal and Potentially Important: Are Phytotoxic Foliage Leachates Overlooked in Plant Invasion Studies?
Authors: Jones Gruffydd , Tomlinson Max , Owen Rhys , Scullion John , Winters Ana , Jenkins Tom , Ratcliffe John , Gwynn-Jones Dylan
Published: March 2019

Invasive species pose a threat to global biodiversity. Recently there has been a growth in research into the chemical aspect of invasions, with some plants reported to introduce compounds to the soil which impair the growth of competing native plants. One such species is Rhododendron ponticum, which has become a damaging invasive shrub in Britain. Here we investigate whether water-soluble compounds introduced from R. ponticum leaves in Ceredigion, Wales, suppressed seed germination, and whether this varied temporally. Leachates from leaf material collected monthly (March to July) were analysed for their chemical composition by liquid chromatography-mass spectrometry and Lactuca sotiva bioassays. In total, 19 compounds were identified, displaying both qualitative and quantitative seasonal variation. Total concentrations peaked in June, however L sativa germination inhibition was only found in leachates from April and May (15% and 17% respectively). The study provides evidence that phytotoxic chemical introduction from R. ponticum leaves is seasonal and most bioactive at a time of year when the seeds of other species germinate. We propose this is one of several mechanisms including shading, lowering of soil pH and the deposition of thick litter, that this species exploits when in competition with other species. We argue that for studies on the phytotoxicity of invasive plants, there is a need to consider temporal variation in the rate and quality of bioactive chemicals produced and released, local precipitation rates, persistence of chemicals in the soil plus synergistic interactions between individual chemicals.
Somatostatin-Expressing Interneurons Co-Release GABA and Glutamate onto Different Postsynaptic Targets in the Striatum
Authors: Cattaneo Stefano , Ripamonti Mattia , Bedogni Francesco , Sessa Alessandro , Taverna Stefano
Published: March 2019

The functional contribution of somatostatin-expressing interneurons (SST-INs) to the synaptic organization of the striatum is poorly understood. Using electrophysiological recordings, optogenetic stimulation, and single-cell PCR analysis, we investigated functional patterns of synaptic connectivity in striatal SST-INs expressing channelrhodopsin-2. Photostimulation of these cells induced both glutamatergic excitatory postsynaptic currents (EPSCs) and GABAergic inhibitory postsynaptic currents (IPSCs) in striatal spiny projection neurons (SPNs) and fast-spiking interneurons (FSIs). The two synaptic components showed equally fast onset latencies, suggesting a mechanism of co-transmission. Accordingly, single-cell PCR analysis revealed that individual striatal SST-INs expressed mRNAs for both glutamate and GABA vesicular transporters (VGLUT1 and VGAT, respectively). During relatively prolonged optical stimuli (0.5-1s), IPSC arrays consistently outlasted EPSCs. As a result, photostimulation of SST-INs caused a transient burst of action potentials followed by a prolonged inhibition in postsynaptic cells.

These data suggest that striatal SST-INs are specialized to locally project synapses exerting a composite excitatory and inhibitory effect through GABA/glutamate co-transmission onto different postsynaptic targets.
Molecular characterization of CHAD domains as inorganic polyphosphate binding modules
Authors: Lorenzo-Orts Laura , Hohmann Ulrich , Zhu Jinsheng , Hothorn Michael
Published: March 2019

Inorganic polyphosphates (polyPs) are long polymers of orthophosphate units (Pi), linked by energy-rich phosphoanhydride bonds. Conserved histidine α-helical (CHAD) domains of unknown biochemical function are often located at the C-terminus of polyP-metabolizing triphosphate tunnel metalloenzymes (TTMs), or can be found as stand-alone proteins in bacterial operons harboring polyP kinases or phosphatases. Here we report that bacterial, archaeal and eukaryotic CHAD domains are specific polyP binding modules. Crystal structures reveal that CHAD domains are formed by two four-helix bundles, giving rise to a central cavity surrounded by two conserved basic surface patches. Different CHAD domains bind polyPs with dissociation constants ranging from the nano-to mid-micromolar range, but not DNA or other Pi-containing ligands. A 2.1 Å CHAD - polyP complex structure reveals the phosphate polymer binding across a central pore and along the two basic patches. Mutational analysis of CHAD – polyP interface residues validates the complex structure and reveals that CHAD domains evolved to bind long-chain polyPs. The presence of a CHAD domain in the polyPase ygiF enhances its enzymatic activity. In plants, CHAD domains bind polyPin vivoand localize to the nucleus and nucleolus, suggesting that plants harbor polyP stores in these compartments. We propose that CHAD domains may be used to engineer the properties of polyP-metabolizing enzymes and to specifically localize polyP stores in eukaryotic cells and tissues.

Significance

A domain of unknown function termed CHAD, present in all kingdoms of life, is characterized as a specific inorganic polyphosphate binding domain. The small size of the domain and its high specificity for inorganic polyphosphates suggest that it could be used as a tool to locate inorganic polyphosphate stores in pro- and eukaryotic cells and tissues.
RedundantSCARECROWgenes pattern distinct cell layers in roots and leaves of maize
Authors: Hughes Thomas E. , Sedelnikova Olga V. , Wu Hao , Becraft Philip W. , Langdale Jane A.
Published: March 2019

The highly efficient C4 photosynthetic pathway is facilitated by ‘Kranz’ leaf anatomy. In Kranz leaves, closely spaced veins are encircled by concentric layers of photosynthetic bundle sheath (inner) and mesophyll (outer) cells. Here we demonstrate that in the C4 monocot maize, Kranz patterning is regulated by redundant function of SCARECROW 1 (ZmSCR1) and a previously uncharacterized homeolog ZmSCR1h.ZmSCR1andZmSCR1htranscripts accumulate in ground meristem cells of developing leaf primordia and inZmscr1;Zmscr1hmutant leaves, most veins are separated by one rather than two mesophyll cells; many veins have sclerenchyma above and/or below instead of mesophyll cells; and supernumerary bundle sheath cells develop. The mutant defects are unified by compromised mesophyll cell development. In addition to Kranz defects,Zmscr1;Zmscr1hmutants fail to form an organized endodermal layer in the root. Collectively, these data indicate that ZmSCR1 and ZmSCR1h redundantly regulate cell-type patterning in both leaves and roots of maize. Leaf and root pathways are distinguished, however, by the cell layer in which they operate – mesophyll at a two-cell distance from leaf veins versus endodermis immediately adjacent to root vasculature.

Summary statement

Two duplicated maizeSCARECROWgenes control the development of the endodermis in roots and the mesophyll in leaves
Increasing the value of raw bulk milk quality based on mammary glands as production units vs. the udder in dairy cows with mastitis
Authors: Leitner Gabriel , Lavon Yaniv , Merin Uzi , Jacoby Shamay , Blum Shlomo E. , Krifucks Oleg , Silanikove Nissim
Published: March 2019

The current study measured the influence of milk of subclinically infected glands by different bacteria species on the cow’s milk and suggests different parameters for milk payment. The effects of bacterial infection or inflammation on gland milk yield were related to the bacteria species that caused the infection. The volume of milk of the inflamed gland from the cow’s milk yield was significantly lower (P<0.001) for the glands previously infected byEscherichia coli(PIEc) and those infected withStreptococcus dysgalactiae.Coagulation properties, rennet clotting time (RCT) and curd firmness (CF) also depended on the bacteria causing the infection. RCT values of all the inflamed glands were significantly longer (P<0.001) and CF values were significantly lower than that of the healthy ones. Moreover, in the whole milk, CF was also significantly lower and not proportional to the volume of the milk from the inflamed gland of the cow’s milk. Calculating the predicted 40% dry matter curd weight (PCW) on the cow level, including the healthy and inflamed glands or the healthy glands alone, found that for 9 of 13 PIEc cows, the presence of the affected gland’s milk in the whole cow milk resulted in a negative PCW value. Likewise, 5 of 20 cows infected byS. dysgalactiaehad negative delta values. Unlike the latter bacteria, PCW from milk of glands infected with CNS increased, although in a lower magnitude than in the healthy glands. No correlation was found between logSCC in the whole cow milk (healthy and inflamed glands) and PCW.
EML4-ALK V3 drives cell migration through NEK9 and NEK7 kinases in non-small-cell lung cancer
Authors: O’Regan Laura , Barone Giancarlo , Adib Rozita , Woo Chang Gok , Jeong Hui Jeong , Richardson Emily L. , Richards Mark W. , Muller Patricia A.J. , Collis Spencer J. , Fennell Dean A. , Choi Jene , Bayliss Richard , Fry Andrew M.
Published: March 2019

EML4-ALK is an oncogenic fusion present in ∼5% lung adenocarcinomas. However, distinct EML4-ALK variants differ in the length of the EML4 microtubule-associated protein encoded within the fusion and are associated with a poorly understood variability in disease progression and therapeutic response. Here, we show that EML4-ALK variant 3, which is linked to accelerated metastatic spread and worse patient outcome, causes microtubule stabilization, formation of extended cytoplasmic protrusions, loss of cell polarity and increased cell migration. Strikingly, this is dependent upon the NEK9 kinase that interacts with the N-terminal region of EML4. Overexpression of wild-type EML4, as well as constitutive activation of NEK9, also perturbs cell morphology and accelerates cell migration in a manner that requires the downstream kinase NEK7 but not ALK activity. Moreover, elevated NEK9 is associated in patients with EML4-ALK V3 expression, as well as reduced progression-free and overall survival. Hence, we propose that EML4-ALK V3 promotes microtubule stabilization through recruitment of NEK9 and NEK7 to increase cell migration and that this represents a novel actionable pathway that drives disease progression in lung cancer.
Fragment-based screening identifies molecules targeting the substrate-binding ankyrin repeat domains of tankyrase
Authors: Pollock Katie , Liu Manjuan , Zaleska Mariola , Pfuhl Mark , Collins Ian , Guettler Sebastian
Published: March 2019

The PARP enzyme and scaffolding protein tankyrase (TNKS, TNKS2) uses its ankyrin repeat clusters (ARCs) to bind a wide range of proteins and thereby controls diverse cellular functions. A number of these are implicated in cancer-relevant processes, including Wnt/β-catenin signaling and telomere maintenance. The ARCs recognise a conserved tankyrase-binding peptide motif (TBM). All currently available tankyrase inhibitors target the catalytic domain and inhibit tankyrase’s poly(ADP-ribosyl)ation function. However, there is emerging evidence that catalysis-independent “scaffolding” mechanisms contribute to tankyrase function. Here we report a fragment-based screening program against tankyrase ARC domains, using a combination of biophysical assays, including differential scanning fluorimetry (DSF) and nuclear magnetic resonance (NMR). We identify fragment molecules that will serve as starting points for the development of tankyrase substrate binding antagonists. Such compounds will enable probing the scaffolding functions of tankyrase, and may, in the future, provide potential alternative therapeutic approaches to inhibiting tankyrase activity in cancer and other conditions.
Decoding mouse behavior to explain single-trial decisions and their relationship with neural activity
Authors: Weissenberger Yves , King Andrew J. , Dahmen Johannes C.
Published: March 2019

Models of behavior typically focus on sparse measurements of motor output over long timescales, limiting their ability to explain momentary decisions or neural activity. We developed data-driven models relating experimental variables to videos of behavior. Applied to mouse operant behavior, they revealed behavioral encoding of cognitive variables. Model-based decoding of videos yielded an accurate account of single-trial behavior in terms of the relationship between cognition, motor output and cortical activity.
Ant collective behavior is heritable and shaped by selection
Authors: Walsh Justin T. , Garnier Simon , Linksvayer Timothy A.
Published: March 2019

Collective behaviors are widespread in nature and usually assumed to be strongly shaped by natural selection. However, the degree to which variation in collective behavior is heritable and has fitness consequences -- the two prerequisites for evolution by natural selection -- is largely unknown. We used a new pharaoh ant (Monomorium pharaonis) mapping population to estimate the heritability, genetic correlations, and fitness consequences of three collective behaviors (foraging, aggression, and exploration) as well as body size, sex ratio, and caste ratio. Heritability estimates for the collective behaviors were moderate, ranging from 0.17 to 0.32, but lower than our estimates for the heritability of caste ratio, sex ratio, and the body size of new workers, queens, and males. Moreover, variation among colonies in collective behaviors was phenotypically correlated, suggesting that selection may shape multiple colony collective behaviors simultaneously. Finally, we found evidence for directional selection that was similar in strength to estimates of selection in natural populations. Altogether, our study begins to elucidate the genetic architecture of collective behavior and is one of the first studies to demonstrate that it is shaped by selection.
Dispersal dynamics and local filtering vary with climate across a grassland landscape
Authors: Guittar John , Goldberg Deborah , Klanderud Kari , Berge Astrid , Boixaderas Marta Ramírez , Meineri Eric , Töpper Joachim , Vandvik Vigdis
Published: March 2019

Dispersal dynamics and local filtering interactively generate regional vegetation patterns, but empirical evidence of their combined influence in nature is scarce, representing a missing link between our theoretical understanding of community assembly and real-world observation. Here, we compare seed and adult plant communities at twelve grassland sites with different climates in southern Norway to explore the degree to which community membership is shaped by dispersal limitation and local niche-based filtering, and how this varies with climate. To do this, we first divide species at each site into two groups: “locally-transient” species, which occur as seeds but are rare or absent as adults (i.e., they arrive but are filtered out), or “locally-persistent” species, which occur consistently as adults in annual vegetation surveys. We then ask questions to reveal where, when, why, and how locally-transient species are systematically disfavored during community assembly. Our results led to four main conclusions: (1) the strength of local filtering on community membership increased with temperature, (2) surprisingly, local filtering was stronger during seedling emergence than during seedling establishment, (3) climate-based niche differences drove differential performance among species, especially for seeds dispersing outside of their realized climate niches into more stressful (colder and drier) climates, and (4) locally-transient species had traits that may made them better dispersers (smaller seeds) but poorer competitors for light (shorter statures, less persistent clonal connections) than locally-persistent species, providing a potential explanation for why they arrived to new sites but failed to establish persistent adult populations. Our study is one of the first to combine seed, seedling, and adult survey data across multiple sites with different climates to provide a rigorous empirical evaluation of the combined influence of dispersal limitation and local filtering on the generation and maintenance of climate-associated vegetation patterns.
Machine-learning a virus assembly fitness landscape
Authors: Dechant Pierre-Philippe , He Yang-Hui
Published: March 2019

Realistic evolutionary fitness landscapes are notoriously difficult to construct. A recent cutting-edge model of virus assembly consists of a dodecahedral capsid with 12 corresponding packaging signals in three affinity bands. This whole genome/phenotype space consisting of 312genomes has been explored via computationally expensive stochastic assembly models, giving a fitness landscape in terms of the assembly efficiency. Using latest machine-learning techniques by establishing a neural network, we show that the intensive computation can be short-circuited in a matter of minutes to astounding accuracy.
FUSALS-causative mutations impactFUSautoregulation and the processing of RNA-binding proteins through intron retention
Authors: Humphrey Jack , Birsa Nicol , Milioto Carmelo , Robaldo David , Eberle Andrea B , Kräuchi Rahel , Bentham Matthew , Ule Agnieszka M. , Jarvis Seth , Bodo Cristian , Garone Maria Giovanna , Devoy Anny , Rosa Alessandro , Bozzoni Irene , Fisher Elizabeth MC , Ruepp Marc-David , Mühlemann Oliver , Schiavo Giampietro , Isaacs Adrian M , Plagnol Vincent , Fratta Pietro
Published: March 2019

Mutations in the RNA-binding protein FUS cause amyotrophic lateral sclerosis (ALS), a devastating neurodegenerative disease in which the loss of motor neurons induces progressive weakness and death from respiratory failure, typically only 3-5 years after onset. FUS plays a role in numerous aspects of RNA metabolism, including mRNA splicing. However, the impact of ALS-causative mutations on splicing has not been fully characterised, as most disease models have been based on FUS overexpression, which in itself alters its RNA processing functions. To overcome this, we and others have recently created knock-in models, and have generated high depth RNA-sequencing data on FUS mutants in parallel to FUS knockout. We combined three independent datasets with a joint modelling approach, allowing us to compare the mutation-induced changes to genuine loss of function. We find that FUS ALS-mutations induce a widespread loss of function on expression and splicing, with a preferential effect on RNA binding proteins. Mutant FUS induces intron retention changes through RNA binding, and we identify an intron retention event in FUS itself that is associated with its autoregulation. Altered FUS regulation has been linked to disease, and intriguingly, we find FUS autoregulation to be altered not only by FUS mutations, but also in other genetic forms of ALS, including those caused by TDP-43, VCP and SOD1 mutations, supporting the concept that multiple ALS genes interact in a regulatory network.
Role of α-Catenin and its mechanosensing properties in the regulation of Hippo/YAP-dependent tissue growth
Authors: Sarpal Ritu , Yan Victoria , Kazakova Lidia , Sheppard Luka , Tepass Ulrich
Published: March 2019

α-catenin is a key protein of adherens junctions (AJs) with mechanosensory properties. It also acts as a tumor suppressor that limits tissue growth. Here we analyzed the function of Drosophila α-Catenin (α-Cat) in growth regulation of the wing epithelium. We found that different α-Cat levels led to a differential activation of Hippo/Yorkie or JNK signaling causing tissue overgrowth or degeneration, respectively. α-Cat can modulate Yorkie-dependent tissue growth through recruitment of Ajuba, a negative regulator of Hippo signaling, to AJs but also through a mechanism that does not involve junctional recruitment of Ajuba. Further, both mechanosensory regions of α-Cat, the M region and the actin-binding domain (ABD), contribute to growth regulation. Whereas M is dispensable for α-Cat function in the wing, individual M domains (M1, M2, M3) have opposing effects on growth regulation. In particular, M1 limits Ajuba recruitment. Loss of M1 cause Ajuba hyper-recruitment to AJs promoting tissue-tension independent overgrowth. Although M1 binds Vinculin, Vinculin it is not responsible for this effect. Moreover, disruption of mechanosensing of the α-Cat actin-binding domain affects tissue growth, with enhanced actin interactions stabilizing junctions and leading to tissue overgrowth. Together, our findings indicate that α-Cat acts through multiple mechanisms to control tissue growth, including regulation of AJ stability, mechanosensitive Ajuba recruitment, and dynamic direct F-actin interactions.
Mapping the human subcortical auditory system using histology, post mortem MRI and in vivo MRI at 7T
Authors: Sitek Kevin Richard , Gulban Omer Faruk , Calabrese Evan , Johnson G. Allan , Lage-Castellanos Agustin , Moerel Michelle , Ghosh Satrajit S. , De Martino Federico
Published: March 2019

Studying the human subcortical auditory system non-invasively is challenging due to its small, densely packed structures deep within the brain. Additionally, the elaborate three-dimensional (3-D) structure of the system can be difficult to understand based on currently available 2-D schematics and animal models. We addressed these issues using a combination of histological data, post mortem magnetic resonance imaging (MRI), and in vivo MRI at 7 Tesla. We created anatomical atlases based on state-of-the-art human histology (BigBrain) and post mortem MRI (50 μm). We measured functional MRI (fMRI) responses to natural sounds and demonstrate that the functional localization of subcortical structures is reliable within individual participants who were scanned in two different experiments. Further, a group functional atlas derived from the functional data locates these structures with a median distance below 2mm. Using diffusion MRI tractography, we revealed structural connectivity maps of the human subcortical auditory pathway both in vivo (1050 μm isotropic resolution) and post mortem (200 μm isotropic resolution). This work captures current MRI capabilities for investigating the human subcortical auditory system, describes challenges that remain, and contributes novel, openly available data, atlases, and tools for researching the human auditory system.
Targeted volumetric single-molecule localization microscopy of defined presynaptic structures in brain sections
Authors: Pauli Martin , Paul Mila M. , Proppert Sven , Sharifi Marzieh , Repp Felix , Kollmannsberger Philip , Sauer Markus , Heckmann Manfred , Sirén Anna-Leena
Published: March 2019

Revealing the molecular organization of anatomically precisely defined brain regions is necessary for the refined understanding of synaptic plasticity. Although, three-dimensional (3D) single-molecule localization microscopy can provide the required molecular resolution, single-molecule imaging more than a few micrometers deep into tissue remains challenging. To quantify presynaptic active zones (AZ) of entire, large, conditional detonator hippocampal mossy fiber (MF) boutons with diameters as large as 10 µm, we developed a method for aberration-free volumetricdirectstochastic optical reconstruction microscopy (dSTORM). An optimized protocol for fast repeated axial scanning and efficient sequential labeling of the AZ scaffold Bassoon and membrane bound GFP with Alexa Fluor 647 enables 3D-dSTORM imaging of 25 µm thick mouse brain sections and assignment of AZs to specific neuronal substructures. Quantitative data analysis revealed large differences in Bassoon cluster size and density for distinct hippocampal regions with largest clusters in MF boutons.
Midgut Transcriptome Analysis ofClostera anachoretaTreated with Cry1Ac Toxin
Authors: Jie Liu , Liucheng Wang , Guona Zhou , Junxia Liu , Baojia Gao
Published: March 2019

Clostera anachoretais one of the important Lepidoptera insect pests in forestry, especially in poplars woods in China, Europe, Japan and India, et al, and also the target insect of Cry1Ac toxin and Bt plants. In this study, by using the different dosages of Btcry1Ac toxin to feed larvae and analyzing the transcriptome data, we found six genes, HSC70, GNB2L/RACK1, PNLIP, BI1-like, arylphorin type 2 and PKM, might be associated with Cry1Ac toxin. And PI3K-Akt pathway, which was highly enriched in DEGs and linked to several crucial pathways, including the B cell receptor signaling pathway, toll-like receptor pathway, and MAPK signaling pathway, might be involved in the recovery stage when response to sub-lethal Cry1Ac toxin. This is the first study conducted to specifically investigateC. anachoretaresponse to Cry toxin stress using large-scale sequencing technologies, and the results highlighted some important genes and pathway that could be involved in Btcry1Ac resistance development or could serve as targets for biologically-based control mechanisms of this insect pest.
Time course of the physiological stress response to an acute stressor and its associations with the primacy and recency effect of the serial position curve
Authors: Becker Linda , Rohleder Nicolas
Published: March 2019

Whether stress affects memory depends on which stress pathway becomes activated and which specific memory system is involved. The activation of the sympathetic nervous system (SNS), leads to a release of catecholamines. The activation of the hypothalamic-pituitary-adrenal (HPA) axis, leads to a release of glucocorticoids. In thus study, it was investigated whether SNS and/or HPA axis activation are associated with long-term memory (LTM) and/or working memory (WM) performance in humans. Thirty-three participants underwent the socially evaluated cold-pressor test. Salivary alpha-amylase (sAA) was used as a marker for the activation of the SNS and cortisol as marker for HPA axis activation. Memory was assessed by means of word lists with 15 words each. The primacy effect (i.e., the correctly recalled words from the beginning of the lists) of the serial position curve was considered as indicator for LTM. The recency effect (i.e., the correctly recalled words from the end of the lists) were used as estimator for WM performance. In sAA responders, the recency effect and, therefore, WM performance increased immediately after the stressor. This was not found in sAA non-responders. In cortisol responders, the primacy effect and, thus, LTM performance decreased 20 minutes after the stressor. No change in LTM performance was found in cortisol non-responders. Our study supports the assumptions that 1) SNS activation is associated with WM processes via stimulation of the prefrontal cortex, and 2) HPA axis activation is associated with LTM processes through interactions with the hippocampus.
HIV-1 co-receptor usage and variable loop contact impacts V3 loop bnAb susceptibility
Authors: Registre Ludy , Moreau Yvetane , Ataca Sila Toksoz , Pulukuri Surya , Henrich Timothy J. , Lin Nina , Sagar Manish
Published: March 2019

In clinical trials, HIV-1 broadly neutralizing antibodies (bnAbs) effectively lower plasma viremia and delay virus reemergence after antiretroviral treatment is stopped among infected individuals that have undetectable virus levels. Presence of less neutralization susceptible strains prior to treatment, however, decreases the efficacy of these antibody-based treatments. The HIV-1 envelope glycoprotein harbors extensive genetic variation, and thus, neutralization sensitivity often cannot be predicted by sequence analysis alone. Sequence-based prediction methods are needed because phenotypic-based assays are labor intensive and not sensitive. Based on the finding that phenotypically confirmed CXCR4- as compared to exclusive CCR5-utilizing strains are less neutralization sensitive, especially to variable loop 1 and 2 (V1-V2) and V3 loop bnAbs, we show that an algorithm that predicts receptor usage identifies envelopes with decreased V3 loop bnAb susceptibility. Homology modeling suggests that the primary V3 loop bnAb epitope is equally accessible among CCR5- and CXCR4-using strains although variants that exclusively use CXCR4 have V3 loop protrusions that interfere with CCR5 receptor interactions. On the other hand, homology modeling also shows that envelope V1 loop orientation interferes with V3 loop directed bnAb binding, and this accounts for decreased neutralization sensitivity in some but not all cases. Thus, there are likely different structural reasons for the co-receptor usage restriction and the differential bnAb susceptibility. Algorithms that use sequence data to predict receptor usage and antibody-envelope homology models can be used to identify variants with decreased sensitivity to V3 loop and potentially other bnAbs.

AUTHOR SUMMARY

HIV-1 broadly neutralizing antibody (bnAb) therapies are effective, but the pre-existence of less susceptible variants may lead to therapeutic failure. Sequence-based methods are needed to predict pre-treatment variants’ neutralization sensitivity. HIV-1 strains that use the CXCR4 as compared to the CCR5 receptor are less neutralization susceptible, especially to V1-V2 and V3 loop bnAbs. A sequence-based algorithm that predicts receptor usage can identify envelope variants with decreased V3 loop bnAb susceptibility. While the inability to utilize the CCR5 receptor maps to a predicted protrusion in the envelope V3 loop, this viral determinant does not directly influence V3 loop bnAb sensitivity. Furthermore, homology modeling predicted contact between the envelope V1 loop and an antibody also impact V3 loop bnAb susceptibility in some but not all cases. An algorithm that predicts receptor usage and homology modeling can be used to predict sensitivity to bnAbs that target the V3 loop and potentially other envelope domains. These sequence-based methods will be useful as HIV-1 bnAbs enter the clinical arena.
Anomalous neutron scattering `halo' observed in highly oriented pyrolytic graphite
Authors: He Lilin , Li Chen , Hamilton William A. , Hong Tao , Tong Xin , Winn Barry L. , Crow Lowell , Bailey Katherine , Gallego Nidia C.
Published: March 2019

Highly oriented pyrolytic graphite (HOPG) has been used as monochromators, analyzers and filters at neutron and X-ray scattering facilities for more than half a century. Interesting questions remain. In this work, the first observation of anomalous neutron `halo' scattering of HOPG is reported. The scattering projects a ring onto the detector with a half-cone angle of 12.4°, which surprisingly persists to incident neutron wavelengths far beyond the Bragg cutoff for graphite (6.71 Å). At longer wavelengths the ring is clearly a doublet with a splitting roughly proportional to wavelength. Sample tilting leads to the shift of the ring, which is wavelength dependent with longer wavelengths providing a smaller difference between the ring shift and the sample tilting. The ring broadens and weakens with decreasing HOPG quality. The lattice dynamics of graphite play a role in causing the scattering ring, as shown by the fact that the ring vanishes once the sample is cooled to 30 K. A possible interpretation by multiple scattering including elastic and inelastic processes is proposed.
A dinuclear phosphite rhodium(I) complex obtained by syngas treatment of a Rh/hydroxy phosphonite olefin hydroformylation precatalyst
Authors: Selent Detlef , Spannenberg Anke , Kubis Christoph , Börner Armin
Published: March 2019

A hydroxy phosphonite was found to be unstable during the catalyst preformation routine applied towards a rhodium olefin hydroformylation catalyst. C—P bond cleavage occurred when the phosphonite was reacted with [(acac)Rh(1,5-COD)] (acac is acetyl acetate and 1,5-COD is cycloocta-1,5-diene) at 80 °C and 20 bar of CO/H2. As a result, a nearly planar six-membered ring structure consisting of two rhodium(I) cations and two bridging phosphorous acid diester anions was formed, namely bis[μ-(4,8-di-tert-butyl-2,10-dimethoxydibenzo[d,f][1,3,2]dioxaphosphepin-6-yl)oxy]-1:2κ2
P:O;1:2κ2
O:P-bis{[6-([1,1′-biphenyl]-2-yloxy)-4,8-di-tert-butyl-2,10-dimethoxydibenzo[d,f][1,3,2]dioxaphosphepine-κP]carbonylrhodium(I)} toluene tetrasolvate, [Rh2(C22H28O5P)2(C34H37O5P)2(CO)2]·4C7H8. Further coordination of phosphite and of carbonyl groups resulted in 16-electron rhodium centres.
Interplay of noncovalent interactions in antiseptic quaternary ammonium surfactant Miramistin
Authors: Dolgushin Fedor M. , Goloveshkin Alexander S. , Ananyev Ivan V. , Osintseva Svetlana V. , Torubaev Yury V. , Krylov Sergey S. , Golub Alexandre S.
Published: March 2019

The molecular and crystal structure of the widely used antiseptic benzyldimethyl{3-[(1-oxotetradecyl)amino]propyl}ammonium chloride monohydrate (Miramistin, MR), C26H47N2O+·Cl−·H2O, was determined by a single-crystal X-ray diffraction study and analyzed in the framework of the QTAIM (quantum theory of atoms in molecules) approach using both periodic and molecular DFT (density functional theory) calculations. The various noncovalent intermolecular interactions of different strengths were found to be realized in the hydrophilic parts of the crystal packing (i.e. O—H...Cl, N—H...Cl, C—H...Cl, C—H...O and C—H...π). The hydrophobic parts are built up exclusively by van der Waals H...H contacts. Quantification of the interaction energies using calculated electron-density distribution revealed that the total energy of the contacts within the hydrophilic and hydrophobic regions are comparable in value. The organic MR cation adopts the bent conformation with the head group tilted back to the long-chain alkyl tail in both the crystalline and the isolated state due to stabilization of this geometry by several intramolecular C—H...π, C—H...N and H...H interactions. This conformation preference is hypothesized to play an important role in the interaction of MR with biomembranes.
Synthesis, crystal structure, spectroscopic features and Hirshfeld surfaces of 2-methyl-3-[(2-methylphenyl)carbamoyl]phenyl acetate
Authors: Yaman Mavişe , Cakmak Şukriye , Dege Necmi , Odabaşoğlu Mustafa , Pavlenko Vadim A. , Kutuk Halil
Published: March 2019

The title compound, C17H17NO3, was synthesized, characterized by IR spectroscopy and its crystal structure was determined from single-crystal diffraction data. The asymmetric unit contains two molecules, which adopt different conformations. In one molecule, the acetoxy and the terminal 2-methylphenyl groups are positioned on opposite sides of the plane formed by the central benzene ring, whereas in the other molecule they lie on the same side of this plane. In the crystal, the molecules are linked through strong N—H...O hydrogen bonds into chains along [010]. Hirshfeld surface analysis and fingerprint plots were used to investigate the intermolecular interactions in the solid state.
International R&D alliances and innovation for emerging market multinationals: roles of environmental turbulence and knowledge transfer
Authors: Liu Yang , Deng Ping , Wei Jiang , Ying Ying , Tian Mu
Published: March 2019

Purpose

The purpose of this paper is to examine the relationships between environment turbulence, knowledge transfer and innovation performance for emerging market multinationals (EMNEs) in an asymmetric international R&D alliance.

Design/methodology/approach

Data were collected through a survey of high-tech firms in Zhejiang Province of China from 2013 to 2015.

Findings

Innovation performance of EMNEs is positively influenced by knowledge transfer activities (knowledge replication and knowledge adaption), technological and market turbulence, while negatively influenced by institutional turbulence. In addition, different aspects of environmental turbulence moderate the relationship between knowledge transfer practices and innovation performance of EMNEs differently.

Research limitations/implications

Future studies could use a longitudinal design to capture the dynamism driving innovation performance of EMNEs through R&D alliances.

Practical implications

Practical guidelines are provided particularly for EMNE managers on how to develop an innovation strategy by leveraging external knowledge, adaptive innovation and environmental turbulence.

Originality/value

This study deepens the knowledge of how EMNEs enhance their innovation by building the linkage between environmental turbulence and absorptive capacity through knowledge transfer activities in an asymmetric international R&D alliance.
Where do we go from here? The future of B2B governance research
Authors: Wathne Kenneth Henning , Fjeldstad Øystein D.
Published: March 2019

Purpose

This paper aims to identify promising areas for future business to business (B2B) governance research.

Design/methodology/approach

This paper uses a theoretical approach.

Findings

Most governance research in marketing is conducted within the context of value chains (Porter 1985). There are great opportunities for governance researchers in marketing to improve the understanding of B2B relationships in problem solving and networking services. Moreover, rapid innovations taking place in networking services are changing the institutional environment across all forms of value creation. This in turn impacts how the nature and governance of relationships in the broader economy are understood.

Originality/value

The literature on B2B relationship governance is primarily rooted in one particular form of value creation, namely, the “value chain” (Porter, 1985). The authors examine whether the current conceptualization of B2B relationship governance is equally applicable for firms that have a different value creation logic and therefore engage in exchange relationships that differ in their object of exchange.
Community services and transforming care: reflections and considerations
Authors: Barnoux Magali
Published: March 2019

Purpose

The purpose of this paper is to consider the existing evidence base regarding community services for people with learning disabilities in the context of transforming care (TC).

Design/methodology/approach

Reflections and commentary on the provision of community services for people with learning disabilities following Washington et al.’s article on admissions and discharges from assessment and treatment units in England.

Findings

The existing evidence base pertaining to community learning disability teams in the UK is dated, sparse and methodologically weak. A greater focus on researching community services for people with learning disabilities is needed in order to inform best practice guidelines.

Originality/value

The success of the TC agenda is contingent on the provision of high quality community services. However, the focus has been on discharging individuals from hospital, rather than the support available to them once they leave.
What Dividend Imputation Means for Retirement Savers
Authors: Butt Adam , Khemka Gaurav , Warren Geoffrey J.
Published: March 2019

We examine the implications for Australian retirees of full access to dividend imputation credits using a stochastic life‐cycle model. We find that the availability of imputation credits can justify a significant bias towards Australian equities in retirement portfolios, largely at the expense of world equities. We also generate estimates of the value of imputation credits to retirees, finding it could potentially support increased consumption during retirement of 5–6 per cent, or equivalent value to a 8–9 per cent higher balance at retirement. Our study enhances the understanding of equity home bias, and provides insights relevant for public policy.