bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase transformations and microstructural evolution of nanocrystalline Ti-18Zr-5Nb-3Sn-4Ta powders through mechanical alloying
Authors: Dercz Grzegorz , Matuła Izabela , Zubko Maciej , Barczyk Jagoda
Published: February 2019

The aims of the present study are to determine the possibility of obtaining a new, nanocrystalline Ti-18Zr-5Nb-3Sn-4Ta at.-% alloy by a ball milling method, and to observe the influence of various milling times on phase composition and structure of the obtained material. The X-ray diffraction results confirmed the alloy synthesis and revealed the presence of α- and β-Ti phases. The Rietveld refinement showed that the production method and the atomic radii of the elements used in the mechanical synthesis have influence on the structure. Scanning electron microscopy observation leads to the conclusion that the powder particles and the degree of aggregation change with increasing milling time.

This paper is part of a Thematic Issue on The Crystallographic Aspects of Metallic Alloys.
Unprompted vigorous physical activity is associated with higher levels of subsequent sedentary behaviour in participants with low cardiorespiratory fitness: a cross‐sectional study
Authors: Skovgaard Esben Lykke , Obling Kirstine , Maindal Helle Terkildsen , Rasmussen Cuno , Overgaard Kristian
Published: February 2019

Performing physical activity is considered health promoting but may induce a need for subsequent rest periods. This study aimed to determine the within‐day interactions between vigorous physical activity (VPA) and sedentary behaviour (SB) in participants with low cardiorespiratory fitness. We tested the hypothesis that VPA is associated with a temporary subsequent increase in SB. One week of accelerometer data containing a minimum of one 10‐min bout of VPA from 62 participants with low cardiorespiratory fitness (31–50 years old) were obtained from the MILE study. A comparison of SB was made between days with a bout of VPA and days without (control). Due to a positive association between VPA and number and duration of sedentary bouts, the time accumulated in both uninterrupted and total sedentary bouts were 27 (95% CI, 10–45) min and 29 (95% CI, 9–50) min higher on VPA days compared to control days (P < 0.05). Our results indicate that in participants with low cardiovascular fitness, unprompted VPA is positively associated with an increase in subsequent sedentary time. We propose that such VPA‐associated sedentary time may be viewed as part of a healthy activity pattern.
Extended Gravity
Authors: Morales Eduardo , Sheu Gloria , Zahler Andrés
Published: February 2019

Exporting firms often enter foreign markets that are similar to their previous export destinations. We develop a dynamic model in which a firm’s exports in a market may depend on how similar the market is to the firm’s home country (gravity) and to its previous export destinations (extended gravity). Given the large number of export paths from which forward-looking firms may choose, we use a moment inequality approach to estimate our model. Our estimates indicate that sharing similarities with a prior export destination in terms of geographic location, language, and income per capita jointly reduces the cost of foreign market entry by 69–90%. Reductions due to geographic location (25–38%) and language (29–36%) have the largest effect. Extended gravity thus has a large impact on export entry costs.
Homologs of Caenorhabditis elegans Chemosensory Genes Have Roles in Behavior and Chemotaxis in the Root-Knot Nematode Meloidogyne incognita
Authors: Shivakumara Tagginahalli N. , Dutta Tushar K. , Chaudhary Sonam , von Reuss Stephan H. , Williamson Valerie M. , Rao Uma
Published: February 2019

Nematode chemosensation is a vital component of their host-seeking behavior. The globally important phytonematode Meloidogyne incognita perceives and responds (via sensory organs such as amphids and phasmids) differentially to various chemical cues emanating from the rhizosphere during the course of host finding. However, compared with the free-living worm Caenorhabditis elegans, the molecular intricacies behind the plant nematode chemotaxis are a yet-unexploited territory. In the present study, four putative chemosensory genes of M. incognita, namely, Mi-odr-1, Mi-odr-3, Mi-tax-2, and Mi-tax-4 were molecularly characterized. Mi-odr-1 mRNA was found to be expressed in the cell bodies of amphidial neurons and phasmids of M. incognita. Mi-odr-1, Mi-odr-3, Mi-tax-2, and Mi-tax-4 transcripts were highly expressed in early life stages of M. incognita, consistent with a role of these genes in host recognition. Functional characterization of Mi-odr-1, Mi-odr-3, Mi-tax-2, and Mi-tax-4 via RNA interference revealed behavioral defects in M. incognita and perturbed attraction to host roots in Pluronic gel medium. Knockdown of Mi-odr-1, Mi-odr-3, Mi-tax-2, and Mi-tax-4 resulted in defective chemotaxis of M. incognita to various volatile compounds (alcohol, ketone, aromatic compound, ester, thiazole, pyrazine), nonvolatiles of plant origin (carbohydrate, phytohormone, organic acid, amino acid, phenolic), and host root exudates in an agar-Pluronic gel–based assay plate. In addition, ascaroside-mediated signaling was impeded by downregulation of chemosensory genes. This new information that behavioral response in M. incognita is modulated by specific olfactory genes can be extended to understand chemotaxis in other nematodes.
Polyphenols from Rheum Roots Inhibit Growth of Fungal and Oomycete Phytopathogens and Induce Plant Disease Resistance
Authors: Gillmeister Marit , Ballert Silvia , Raschke Anja , Geistlinger Joerg , Kabrodt Kathrin , Baltruschat Helmut , Deising Holger B. , Schellenberg Ingo
Published: February 2019

A growing world population requires an increase in the quality and quantity of food production. However, field losses due to biotic stresses are currently estimated to be between 10 and 20% worldwide. The risk of resistance and strict pesticide legislation necessitate innovative agronomical practices to adequately protect crops in the future, such as the identification of new substances with novel modes of action. In the present study, liquid chromatography mass spectrometry was used to characterize Rheum rhabarbarum root extracts that were primarily composed of the stilbenes rhaponticin, desoxyrhaponticin, and resveratrol. Minor components were the flavonoids catechin, epicatechin gallate, and procyanidin B1. Specific polyphenolic mixtures inhibited mycelial growth of several phytopathogenic fungi and oomycetes. Foliar spray applications with fractions containing stilbenes and flavonoids inhibited spore germination of powdery mildew in Hordeum vulgare with indications of synergistic interactions. Formulated extracts led to a significant reduction in the incidence of brown rust in Triticum aestivum under field conditions. Arabidopsis thaliana mutant and quantitative reverse-transcription polymerase chain reaction studies suggested that the stilbenes induce salicylic acid-mediated resistance. Thus, the identified substances of Rheum roots represent an excellent source of antifungal agents that can be used in horticulture and agriculture.
Proximity sensors on common noctule bats reveal evidence that mothers guide juveniles to roosts but not food
Authors: Ripperger Simon , Günther Linus , Wieser Hanna , Duda Niklas , Hierold Martin , Cassens Björn , Kapitza Rüdiger , Koelpin Alexander , Mayer Frieder
Published: February 2019

Female bats of temperate zones often communally rear their young, which creates ideal conditions for naive juveniles to find or learn about resources via informed adults. However, studying social information transfer in elusive and small-bodied animals in the wild is difficult with traditional tracking techniques. We used a novel ‘next-generation’ proximity sensor system (BATS) to investigate if and how juvenile bats use social information in acquiring access to two crucial resources: suitable roosts and food patches. By tracking juvenile–adult associations during roost switching and foraging, we found evidence for mother-to-offspring information transfer while switching roosts but not during foraging. Spatial and temporal patterns of encounters suggested that mothers guided juveniles between the juvenile and the target roost. This roost-switching behaviour provides evidence for maternal guidance in bats, a form of maternal care that has long been assumed, but never documented. We did not find evidence that mothers guide the offspring to foraging sites. Foraging bats reported brief infrequent meetings with other tagged bats that were best explained by local enhancement. Our study illustrates how this recent advance in automated biologging provides researchers with new insights into longstanding questions in behavioural biology.
‘Clickable lectins’: bioorthogonal reactive handles facilitate the directed conjugation of lectins in a modular fashion
Authors: Tobola Felix , Sylvander Elise , Gafko Claudia , Wiltschi Birgit
Published: February 2019

Lectins are carbohydrate-binding proteins with specificity for their target ligands. They play diverse roles in cellular recognition and signalling processes, as well as in infections and cancer metastasis. Owing to their specificity, lectins find application in biotechnology and medicine, e.g. for blood group typing, purification of glycoproteins or lipids and as markers that target cancer cells. For some applications, lectins are immobilized on a solid support, or they are conjugated with other molecules. Classical protein conjugation reactions at nucleophilic amino acids such as cysteine or lysine are often non-selective, and the site of conjugation is difficult to pre-define. Random conjugation, however, can interfere with protein function. Therefore, we sought to equip lectins with a unique reactive handle, which can be conjugated with other molecules in a pre-defined manner. We site-specifically introduced non-canonical amino acids carrying bioorthogonal reactive groups into several lectins. As a proof of principle, we conjugated these ‘clickable lectins’ with small molecules. Furthermore, we conjugated lectins with different ligand specificities with one another to produce superlectins. The ‘clickable lectins’ might be useful for any process where lectins shall be conjugated with another module in a selective, pre-defined and site-specific manner.
Prostate-specific antigen glycoprofiling as diagnostic and prognostic biomarker of prostate cancer
Authors: Tkac Jan , Gajdosova Veronika , Hroncekova Stefania , Bertok Tomas , Hires Michal , Jane Eduard , Lorencova Lenka , Kasak Peter
Published: February 2019

The initial part of this review details the controversy behind the use of a serological level of prostate-specific antigen (PSA) for the diagnostics of prostate cancer (PCa). Novel biomarkers are in demand for PCa diagnostics, outperforming traditional PSA tests. The review provides a detailed and comprehensive summary that PSA glycoprofiling can effectively solve this problem, thereby considerably reducing the number of unnecessary biopsies. In addition, PSA glycoprofiling can serve as a prognostic PCa biomarker to identify PCa patients with an aggressive form of PCa, avoiding unnecessary further treatments which are significantly life altering (incontinence or impotence).
In vitro
cell migration quantification method for scratch assays
Authors: Bobadilla Ana Victoria Ponce , Arévalo Jazmine , Sarró Eduard , Byrne Helen M. , Maini Philip K. , Carraro Thomas , Balocco Simone , Meseguer Anna , Alarcón Tomás
Published: February 2019

The scratch assay is an
in vitro
technique used to assess the contribution of molecular and cellular mechanisms to cell migration. The assay can also be used to evaluate therapeutic compounds before clinical use. Current quantification methods of scratch assays deal poorly with irregular cell-free areas and crooked leading edges which are features typically present in the experimental data. We introduce a new migration quantification method, called ‘monolayer edge velocimetry’, that permits analysis of low-quality experimental data and better statistical classification of migration rates than standard quantification methods. The new method relies on quantifying the horizontal component of the cell monolayer velocity across the leading edge. By performing a classification test on
in silico
data, we show that the method exhibits significantly lower statistical errors than standard methods. When applied to
in vitro
data, our method outperforms standard methods by detecting differences in the migration rates between different cell groups that the other methods could not detect. Application of this new method will enable quantification of migration rates from
in vitro
scratch assay data that cannot be analysed using existing methods.
First record of sexual size dimorphism in fossil Strombidae (Mollusca, Gastropoda) from the Miocene of Kutch, western India and its evolutionary implications
Authors: Halder Kalyan , Paira Somnath
Published: February 2019

Persististrombus deperditus(Sowerby) from the Lower Miocene of Kutch, Gujarat, western India is represented by two size classes in our collection. Statistical analyses discriminate the size morphs. Large size variations generally result from either (1) sexual differences or (2) ecophenotypic causes. All the living species of the family Strombidae, wherever examined, are characterized by sexual size dimorphism (SSD).Persististrombus deperditusshares all the characters of SSD in these recent species. Size variations due to difference in ecological factors generally occur in allopatric populations. Similar variations are known to characterize sympatric sub-populations of molluscs living only in the intertidal zone, where upper and lower shorefaces differ significantly in physico-chemical and biological properties.Persististrombus deperdituscomes from a stable shelf setting that received less siliciclastic input in response to transgression. Hence, its size dimorphism is considered to have sexual origin. This is the first report of SSD in a fossil strombid gastropod. It is argued that fecundity selection was the primary driving force behind the evolution of SSD in this gonochoristic gastropod species. Hence, the larger morph is the female.
Modelling the transmission dynamics of
Campylobacter
in Ontario, Canada, assuming house flies,
Musca domestica
, are a mechanical vector of disease transmission
Authors: Cousins Melanie , Sargeant Jan M. , Fisman David , Greer Amy L.
Published: February 2019

Campylobacter
's complicated dynamics and multiple transmission routes have made it difficult to describe using a mathematical framework. Vector-borne disease transmission has been proposed as a potential transmission route of
Campylobacter
with house flies acting as a mechanical vector. This study aimed to (i) determine if a basic
SIR
compartment model that included flies as a mechanical vector and incorporated a seasonally forced environment compartment could be used to capture the observed disease dynamics in Ontario, Canada, and (ii) use this model to determine potential changes to campylobacteriosis incidence using predicted changes to fly population size and fly activity under multiple climate change scenarios. The model was fit to 1 year of data and validated against 8 and 12 years of data. It accurately captured the observed incidence. We then explored changes in human disease incidence under multiple climate change scenarios. When fly activity levels were at a 25% increase, our model predicted a 28.15% increase in incidence by 2050 using the medium–low emissions scenario and 30.20% increase using the high emissions scenario. This model demonstrates that the dynamics of
Campylobacter
transmission can be captured by a model that assumes that the primary transmission of the pathogen occurs via insect vectors.
Impact of uniaxial tensile fatigue on the evolution of microscopic and mesoscopic structure of carbon black filled natural rubber
Authors: Sun Chong , Du Zhongjin , Nagarajan Selvaraj , Zhao Hongying , Wen Shipeng , Zhao Suhe , Zhang Ping , Zhang Liqun
Published: February 2019

This investigation addresses the evolution of the microscopic and mesoscopic structures distribution, and micro-defects of carbon black (CB) filled natural rubber (NR) under uniaxial tensile condition during the fatigue process. NR was filled with three different grades of CB in order to understand the impact of the structural degree and specific surface areas of CB and fatigue degree on the Payne effect. It was found that the Payne effect was initially suppressed and then enhanced by increasing the degree of fatigue. The decrease of the storage modulus in the low strain area was attributed to the CB network destruction and the breakdown of the matrix cross-linking network in the early fatigue stage. However, by further increasing the degree of fatigue, the spatial rearrangement of CB aggregates with the orientation of molecular chains between adjacent CB aggregates will results in mechanical reinforcement before the appearance of micro-defects. Moreover, it has been demonstrated that the structural degree of CB has a stronger impact on the mesoscopic structures than the specific surface area of CB during the tensile fatigue process.
Disruptive coloration and binocular disparity: breaking camouflage
Authors: Adams Wendy J. , Graf Erich W. , Anderson Matt
Published: February 2019

Many species employ camouflage to disguise their true shape and avoid detection or recognition. Disruptive coloration is a form of camouflage in which high-contrast patterns obscure internal features or break up an animal's outline. In particular, edge enhancement creates illusory, or ‘fake’ depth edges within the animal's body. Disruptive coloration often co-occurs with background matching, and together, these strategies make it difficult for an observer to visually segment an animal from its background. However, stereoscopic vision could provide a critical advantage in the arms race between perception and camouflage: the depth information provided by binocular disparities reveals the true three-dimensional layout of a scene, and might, therefore, help an observer to overcome the effects of disruptive coloration. Human observers located snake targets embedded in leafy backgrounds. We analysed performance (response time) as a function of edge enhancement, illumination conditions and the availability of binocular depth cues. We confirm that edge enhancement contributes to effective camouflage: observers were slower to find snakes whose patterning contains ‘fake’ depth edges. Importantly, however, this effect disappeared when binocular depth cues were available. Illumination also affected detection: under directional illumination, where both the leaves and snake produced strong cast shadows, snake targets were localized more quickly than in scenes rendered under ambient illumination. In summary, we show that illusory depth edges, created via disruptive coloration, help to conceal targets from human observers. However, cast shadows and binocular depth information improve detection by providing information about the true three-dimensional structure of a scene. Importantly, the strong interaction between disparity and edge enhancement suggests that stereoscopic vision has a critical role in breaking camouflage, enabling the observer to overcome the disruptive effects of edge enhancement.
The origins of novelty from within the confines of homology: the developmental evolution of the digging tibia of dung beetles
Authors: Linz David M. , Hu Yonggang , Moczek Armin P.
Published: February 2019

Understanding the origin of novel complex traits is among the most fundamental goals in evolutionary biology. The most widely used definition of novelty in evolution assumes the absence of homology, yet where homology ends and novelty begins is increasingly difficult to parse asevo devocontinuously revises our understanding of what constitutes homology. Here, we executed a case study to explore the earliest stages of innovation by examining the tibial teeth of tunnelling dung beetles. Tibial teeth are a morphologically modest innovation, composed of relatively simple body wall projections and contained fully within the fore tibia, a leg segment whose own homology status is unambiguous. We first demonstrate that tibial teeth aid in multiple digging behaviours. We then show that the developmental evolution of tibial teeth was dominated by the redeployment of locally pre-existing gene networks. At the same time, we find that even at this very early stage of innovation, at least two genes that ancestrally function in embryonic patterning and thus entirely outside the spatial and temporal context of leg formation, have already become recruited to help shape the formation of tibial teeth. Our results suggest a testable model for how developmental evolution scaffolds innovation.
Beyond the visual: using metabarcoding to characterize the hidden reef cryptobiome
Authors: Carvalho Susana , Aylagas Eva , Villalobos Rodrigo , Kattan Yasser , Berumen Michael , Pearman John K.
Published: February 2019

In an era of coral reef degradation, our knowledge of ecological patterns in reefs is biased towards large conspicuous organisms. The majority of biodiversity, however, inhabits small cryptic spaces within the framework of the reef. To assess this biodiverse community, which we term the ‘reef cryptobiome’, we deployed 87 autonomous reef monitoring structures (ARMS), on 22 reefs across 16 degrees latitude of the Red Sea. Combining ARMS with metabarcoding of the mitochondrial cytochrome oxidase I gene, we reveal a rich community, including the identification of 14 metazoan phyla within 10 416 operational taxonomic units (OTUs). While mobile and sessile subsets were similarly structured along the basin, the main environmental driver was different (particulate organic matter and sea surface temperature, respectively). Distribution patterns of OTUs showed that only 1.5% were present in all reefs, while over half were present in a single reef. On both local and regional scales, the majority of OTUs were rare. The high heterogeneity in community patterns of the reef cryptobiome has implications for reef conservation. Understanding the biodiversity patterns of this critical component of reef functioning will enable a sound knowledge of how coral reefs will respond to future anthropogenic impacts.
Geography of speciation affects rate of trait divergence in haemulid fishes
Authors: Tavera José J. , Wainwright Peter C.
Published: February 2019

Speciation and the interactions between recently diverged species are thought to be major causes of ecological and morphological divergence in evolutionary radiations. Here, we explore the extent to which geographical overlap and time since speciation may promote divergence in marine species, which represent a small fraction of currently published studies about the patterns and processes of speciation. A time-calibrated molecular phylogeny of New World haemulid fishes, a major radiation of reef and shore fishes in the tropical West Atlantic and East Pacific, reveals 21 sister species pairs, of which eight are fully sympatric and 13 are allopatric. Sister species comparisons show a non-significant relation between most of the phenotypic traits and time since divergence in allopatric taxa. Additionally, we find no difference between sympatric and allopatric pairs in the rate of divergence in colour pattern, overall body shape, or functional morphological traits associated with locomotion or feeding. However, sympatric pairs show a significant decrease in the rate of divergence in all of these traits with increasing time since their divergence, suggesting an elevated rate of divergence at the time of speciation, the effect of which attenuates as divergence time increases. Our results are consistent with an important role for geographical overlap driving phenotypic divergence early in the speciation process, but the lack of difference in rates between sympatric and allopatric pairs indicates that the interactions between closely related species are not dominant drivers of this divergence.
Linguistic laws in chimpanzee gestural communication
Authors: Heesen Raphaela , Hobaiter Catherine , Ferrer-i-Cancho Ramon , Semple Stuart
Published: February 2019

Studies testing linguistic laws outside language have provided important insights into the organization of biological systems. For example, patterns consistent with Zipf's law of abbreviation (which predicts a negative relationship between word length and frequency of use) have been found in the vocal and non-vocal behaviour of a range of animals, and patterns consistent with Menzerath's law (according to which longer sequences are made up of shorter constituents) have been found in primate vocal sequences, and in genes, proteins and genomes. Both laws have been linked to compression—the information theoretic principle of minimizing code length. Here, we present the first test of these laws in animal gestural communication. We initially did not find the negative relationship between gesture duration and frequency of use predicted by Zipf's law of abbreviation, but this relationship was seen in specific subsets of the repertoire. Furthermore, a pattern opposite to that predicted was seen in one subset of gestures—whole body signals. We found a negative correlation between number and mean duration of gestures in sequences, in line with Menzerath's law. These results provide the first evidence that compression underpins animal gestural communication, and highlight an important commonality between primate gesturing and language.
Cost of dispersal in a social mammal: body mass loss and increased stress
Authors: Maag Nino , Cozzi Gabriele , Bateman Andrew , Heistermann Michael , Ganswindt André , Manser Marta , Clutton-Brock Tim , Ozgul Arpat
Published: February 2019

Dispersal is a key process influencing the dynamics of socially and spatially structured populations. Dispersal success is determined by the state of individuals at emigration and the costs incurred after emigration. However, quantification of such costs is often difficult, due to logistical constraints of following wide-ranging individuals. We investigated the effects of dispersal on individual body mass and stress hormone levels in a cooperative breeder, the meerkat (Suricata suricatta). We measured body mass and faecal glucocorticoid metabolite (fGCM) concentrations from 95 dispersing females in 65 coalitions through the entire dispersal process. Females that successfully settled lost body mass, while females that did not settle but returned to their natal group after a short period of time did not. Furthermore, dispersing females had higher fGCM levels than resident females, and this was especially pronounced during the later stages of dispersal. By adding information on the transient stage of dispersal and by comparing dispersers that successfully settled to dispersers that returned to their natal group, we expand on previous studies focusing on the earlier stages of dispersal. We propose that body mass and stress hormone levels are good indicators to investigate dispersal costs, as these traits often play an important role in mediating the effects of the environment on other life-history events and individual fitness.
Lysobacter psychrotolerans sp. nov., isolated from soil in the Tianshan Mountains, Xinjiang, China
Authors: Luo Yang , Dong Hongqiang , Zhou Meng , Huang Yaolong , Zhang Hua , He Wenliang , Sheng Hongmei , An Lizhe
Published: February 2019

A novel aerobic bacterial strain, designated ZS60T, with long, rod-shaped, Gram-staining-negative, aerobic cells was isolated from the soil in the Tianshan Mountains, Xinjiang, China. Phylogenetic analysis based on its 16S rRNA gene sequence indicated that strain ZS60T was affiliated with the genus

Lysobacter

, and was most closely related to

Lysobacter daejeonensis

GH1-9T (96.9 %),

Lysobacter caeni

BUT-8T (96.8 %) and

Lysobacter ruishenii

CTN-1T (96.7 %). The average nucleotide identity values between strain ZS60T,

L. daejeonensis

GH1-9T and

L. ruishenii

CTN-1T were 78.14 and 78.39 %, respectively. The DNA–DNA relatedness between strain ZS60T,

L. daejeonensis

GH1-9T and

L. caeni

BUT-8T were 44.8 and 39.1 %, respectively. The genomic DNA G+C content of the strain ZS60T was 67.7 mol% (draft genome sequence), and Q-8 was the predominant ubiquinone. The major cellular fatty acids of strain ZS60T were iso-C15 : 0 (23.4 %), iso-C17 : 0 (17.2 %) and iso-C17 : 1
 ω9c (12.6 %). On the basis of genotypic, phenotypic and biochemical data, strain ZS60T is considered to represent a novel species of the genus

Lysobacter

, for which the name

Lysobacter
psychrotolerans sp. nov. is proposed. The type strain is ZS60T (=CGMCC 1.15509T=NBRC 112614T).
Conditional activation of immune-related signatures and prognostic significance: a pan-cancer analysis
Authors: Roelands Jessica , Hendrickx Wouter , Mall Raghvendra , Saad Mohamad , Halliwill Kyle , Zoppoli Gabriele , Curigliano Giuseppe , Rinchai Darawan , Decock Julie , Delogu Lucia G , Chouchane Lotfi , Wang Ena , Kuppen Peter , Finetti Pascal , Bertucci Francois , Miller Lance D , Galon Jerome , Marincola Francesco M , Ceccarelli Michele , Bedognetti Davide
Published: February 2019

Background

It is becoming clear that tumor immune T cell infiltration and its functional orientation have substantial effect on cancer progression, influencing both response to therapy and prognosis. In this pan-cancer study, the previously described Immunologic Constant of Rejection (ICR) signature is used to define opposing immune phenotypes (i.e., immuneactive and immune-silent) across 31 different histologies. We systematically analyze the interconnections between the genetic programming of neoplasms and their immune orientation across different histologies, and the prognostic impact of such interplay. Moreover, we investigated the predictive value of ICR classification across various public datasets of immune checkpoint inhibition therapy.

Methods

RNA-seq data of samples from a total of 9,282 patient tumor samples representing 31 cancer types were obtained from The Cancer Genome Atlas (TCGA). We classified each cancer type based on the expression of the ICR gene signature. Oncogenic pathway gene set enrichment and mutational status were analyzed in relation to ICR phenotypes. To explore whether tumorintrinsic attributes associate with the prognostic value of ICR across cancers, we compared mutational load, oncogenic alterations and expression of oncogenic pathways between cancer types using an integrative bioinformatic pipeline.

Results

Our analyses identified a distinct prognostic connotation of ICR depending on cancer histology. We identified several oncogenic pathways whose enrichment inversely correlated with ICR in multiple tumor types. We found several cancer specific pathways that were differentially enriched between tumors in which ICR had a prognostic impact versus the ones in which ICR did not bear any prognostic connotation such as proliferation and TGF-beta signaling. Importantly, this conditional impact of ICR was also validated in the context of immune checkpoint inhibition treatment.

Conclusions

We identified tumor-intrinsic attributes that correlate with immune phenotypes and potentially influence their development. In addition, a relationship was observed between the enrichment of oncogenic pathways and the prognostic significance of the ICR and its predictive value for patients treated with anti-CTLA4 immune checkpoint inhibition. Such information can be used to prioritize potential candidates for therapies aimed at converting immune-silent into immuneactive tumors and to refine stratification algorithms.
The making of an olfactory specialist
Authors: Auer Thomas O. , Khallaf Mohammed A. , Silbering Ana F. , Zappia Giovanna , Ellis Kaitlyn , Hansson Bill S. , Jefferis Gregory S.X.E. , Caron Sophie , Knaden Markus , Benton Richard
Published: February 2019

The evolution of animal behaviour is poorly understood. Despite numerous correlations of behavioural and nervous system divergence, demonstration of the genetic basis of interspecific behavioural differences remains rare. Here we develop a novel neurogenetic model,Drosophila sechellia, a close cousin ofD. melanogasterthat displays profound behavioural changes linked to its extreme host fruit specialisation. Through calcium imaging, we identify olfactory pathways detecting host volatiles. Mutational analysis indicates roles for individual receptors in long- and short-range attraction. Cross-species allele transfer demonstrates that differential tuning of one receptor is important for species-specific behaviour. We identify the molecular determinants of this functional change, and characterise their behavioural significance and evolutionary origin. Circuit tracing reveals that receptor adaptations are accompanied by increased sensory pooling onto interneurons and novel central projection patterns. This work links molecular and neuronal changes to behavioural divergence and defines a powerful model for investigating nervous system evolution and speciation.
Robust network inference using response logic
Authors: Gross Torsten , Wongchenko Matthew , Yan Yibing , Blüthgen Nils
Published: February 2019

Motivation

A major challenge in molecular and cellular biology is to map out the regulatory networks of cells. As regulatory interactions can typically not be directly observed experimentally, various computational methods have been proposed to disentangling direct and indirect effects. Most of these rely on assumptions that are rarely met or cannot be adapted to a given context.

Results

We present a network inference method that is based on a simple response logic with minimal presumptions. It requires that we can experimentally observe whether or not some of the system’s components respond to perturbations of some other components, and then identifies the directed networks that most accurately account for the observed propagation of the signal. To cope with the intractable number of possible networks, we developed a logic programming approach that can infer networks of hundreds of nodes, while being robust to noisy, heterogeneous or missing data. This allows to directly integrate prior network knowledge and additional constraints such as sparsity. We systematically benchmark our method on KEGG pathways, and show that it outperforms existing approaches in DREAM3 and DREAM4-challenges. Applied to a perturbation data set on PI3K and MAPK pathways in isogenic models of a colon cancer cell line, it generates plausible network hypotheses that explain distinct sensitivities towards EGFR inhibitors by different PI3K mutants.

Availability and Implementation

A Python/Answer Set Programming implementation can be accessed at github.com/GrossTor/response-logic.

Contact

nils.bluethgen@charite.de
The IL-12– and IL-23–Dependent NK-Cell Response is Essential for Protective Immunity Against SecondaryToxoplasma GondiiInfection
Authors: Ivanova Daria L. , Mundhenke Tiffany M. , Gigley Jason P.
Published: February 2019

Natural Killer (NK) cells can develop memory-like features and contribute to long-term immunity in mice and humans. NK cells are critical for protection against acuteT. gondiiinfection. However, whether they contribute to long-term immunity in response to this parasite is unknown. We used a vaccine challenge model of parasite infection to address this question and to define the mechanism by which NK cells are activated during secondary parasite infection. We found NK cells were required for control of secondary infection. NK cells increased in number at the infection site, became cytotoxic and produced IFNγ. Adoptive transfer and NK-cell fate mapping revealed thatT. gondii–experienced NK cells were not intrinsically different from naïve NK cells with respect to their long-term persistence and ability to protect. Thus, they did not develop memory-like characteristics. Instead, a cell-extrinsic mechanism may control protective NK-cell responses during secondary infection. To test the involvement of a cell-extrinsic mechanism, we used anti-IL-12p70 and IL-12p35-/-mice and found that the secondary NK-cell response was not fully dependent on IL-12. IL-23 depletion with anti-IL-23p19in vivosignificantly reduced the secondary NK-cell response, suggesting that both IL-12 and IL-23 were involved. Anti-IL-12p40 treatment, which blocks both IL-12 and IL-23, eliminated the protective secondary NK-cell response, supporting this hypothesis. Our results define a previously unknown protective role for NK cells during secondaryT. gondiiinfection that is dependent on IL-12 and IL-23.
White matter changes in the perforant path in patients with amyotrophic lateral sclerosis
Authors: Mollink J. , Hiemstra M. , Miller K.L. , Huszar I.N. , Jenkinson M. , Raaphorst J. , Wiesmann M. , Ansorge O. , Pallebage-Gamarallage M. , van Cappellen van Walsum A.M.
Published: February 2019

Amyotrophic lateral sclerosis (ALS) is a progressive and incurable motor neuron disease. Some ALS patients are affected by a level of cognitive or behavioural decline that meets the criteria for frontotemporal dementia (FTD). ALS and FTD share genetic and pathological features; for example, the deposition of phosphorylated 43 kDa TAR DNA-binding protein (pTDP-43) in the brain. Spreading of pTDP-43 pathology in ALS towards brain areas that connect via the Papez circuit is a possible indicator of progression towards FTD. For example, pTDP-43 aggregates in the granule cells of the hippocampus correlate well with clinically manifest FTD. Here, we test the hypothesis that white matter degeneration of the perforant path – as part of the Papez circuit – in the hippocampus is a feature of ALS, even in the absence of fully developed FTD or deposition of pTDP-43 inclusions in hippocampal granule cells. We used diffusion MRI (dMRI), polarized light imaging (PLI) and immunohistochemical analysis of hippocampus sections from controls (n=5) and ALS patients (n=14) to perform an in-depth study of white matter in the perforant path.

The dMRI results show a significant decrease in fractional anisotropy (p=0.01) and an increase in mean diffusivity (p=0.01), axial diffusivity (p=0.03) and radial diffusivity (p=0.03) in the perforant path in ALS patients compared to controls, possibly indicating a loss of white matter fibres. Myelin density (measured with PLI retardance) was lower in ALS patients compared to controls (p=0.05) and correlated with dMRI fractional anisotropy (r=0.52, p=0.03). The dMRI and PLI results were confirmed by the immunohistochemistry; both myelin (proteolipid protein, p=0.03) and neurofilaments (SMI-312, p=0.02) were lower in ALS patients. The activated microglial (CD68) density was similar in ALS and controls. Only two out of the fourteen ALS cases showed pTDP-43 pathology in the dentate gyrus; however, while these two ALS-FTD cases showed reduced myelination in the perforant path, the values were comparable to other ALS cases.

We conclude that degeneration of the perforant path occurs in ALS patients and that this may occur before, or independent of, pTDP-43 aggregation in the dentate gyrus of the hippocampus. Future research should focus on correlating the degree of clinically observed cognitive decline to the amount of white matter atrophy in the perforant path.
Silicone Oil-Induced Ocular Hypertension in Mouse Models Glaucomatous Neurodegeneration and Neuroprotection
Authors: Zhang Jie , Li Liang , Huang Haoliang , Webber Hannah C. , Zhuang Pei , Liu Liang , Dalal Roopa , Tang Peter H. , Mahajan Vinit B. , Sun Yang , Li Shaohua , Zhang Mingchang , Goldberg Jeffrey Louis , Hu Yang
Published: February 2019

Understanding the molecular mechanism of glaucoma and development of neuroprotectants are significantly hindered by the lack of a reliable animal model that accurately recapitulates human glaucoma. Here we sought to develop a mouse model for the secondary glaucoma that is often observed in humans after silicone oil (SO) blocks the pupil or migrates into the anterior chamber following vitreoretinal surgery. We observed similar intraocular pressure (IOP) elevation after intracameral injection into mouse eyes of SO, and removing the SO allows the IOP level to quickly return to normal. This simple, inducible and reversible mouse model showed dynamic changes of visual function that correlate with progressive RGC loss and axon degeneration. We also used a single AAV vector for the first time to co-express miRNA-based shRNA and a neuroprotective transgene and further validated this model as an effective in vivo means to test neuroprotective therapies by targeting neuronal endoplasmic reticulum stress.
Lotus japonicus symbiosis signaling genes and their role in the establishment of root-associated bacterial and fungal communities
Authors: Zgadzaj Rafal , Thiergart Thorsten , Bozsóki Zoltán , Garrido-Oter Ruben , Radutoiu Simona , Schulze-Lefert Paul
Published: February 2019

The wild legume Lotus japonicus engages in mutualistic symbiotic relationships with arbuscular mycorrhiza (AM) fungi and nitrogen-fixing rhizobia. Using plants grown in natural soil and community profiling of bacterial 16S rRNA genes and fungal internal transcribed spacers (ITS), we examined here the role of the Lotus symbiosis genes RAM1, NFR5, SYMRK, and CCaMK in structuring bacterial and fungal root-associated communities. We found host genotype-dependent community shifts in the root and rhizosphere compartments that were mainly confined to bacteria in nfr5 or fungi in ram1 mutants, whilst symRK and ccamk plants displayed major changes across both microbial kingdoms. We observed in all AM mutant roots an almost complete depletion of a large number of Glomeromycota taxa that was accompanied by a concomitant enrichment of Helotiales and Nectriaceae fungi, suggesting compensatory niche replacement within the fungal community. A subset of Glomeromycota whose colonization is strictly dependent on the common symbiosis pathway was retained in ram1 mutants, indicating that RAM1 is dispensable for intraradical colonization by some Glomeromycoyta fungi. However, intraradical colonization by certain Burkholderiaceae taxa is dependent on AM root infection, thereby revealing a microbial interkingdom interaction. Our findings imply a broad role for Lotus symbiosis genes in structuring the root microbiota.
Deep proteomic analysis of Dnmt1 mutant/hypomorphic colorectal cancer cells reveals dys-regulation of Epithelial-Mesenchymal Transition and subcellular re-localization of Beta-Catenin
Authors: Bowler Emily H , Smith-Vidal Alex , Lester Alex , Bell Joseph , Wang Zhenghe , Bell Chris , Wang Yihua , Divecha Nullin , Skipp Paul , Ewing Rob M.
Published: February 2019

Background

DNA methyltransferase I is the primary eukaryotic DNA methyltransferase engaged in maintenance of CpG DNA methylation patterns across the genome. Alteration of CpG methylation patterns and levels is a frequent and significant occurrence across many cancers, and targeted inhibition of Dnmt1 has become an approach of choice for select malignancies. There has been significant interest both in the methyltransferase activity as well as methylation-independent functions of Dnmt1. A previously generated hypomorphic allele of Dnmt1 in HCT116 colorectal cancer cells has become an important tool for understanding Dnmt1 function and how CpG methylation patterns are modulated across the genome. Colorectal cancer cells with the Dnmt1 hypomorphic allele carry a homozygous deletion of exons 3 to 5 of Dnmt1, resulting in greatly reduced Dnmt1 protein expression whilst still exhibiting a limited functional activity and methyltransferase ability. Although this cell model of reduced Dnmt1 levels and function have been used to study the downstream effects on the epigenome and transcriptome, the broader effects of the Dnmt1 hypomorph on the proteome and wider cell signalling are largely unknown.

Results

In this study, we used quantitative proteomic analysis of nuclear-enriched samples of HCT116 Dnmt1 hypomorph cells to identify signalling pathways and processes dysregulated in the hypomorph cells as compared to wild-type HCT116 cells. Unexpectedly, we observed a clear signature of increased expression of Epithelial-to-Mesenchymal (EMT) in Dnmt1 hypomorph cells. We also observed reduced expression and sub-cellular re-localization of Beta-Catenin in Dnmt1 hypomorph cells. Expression of wild-type Dnmt1 in hypomorph cells or knock-down of wild-type Dnmt1 did not recapitulate or rescue the observed protein profiles in Dnmt1 hypomorph cells suggesting that hypomorphic Dnmt1 causes changes not solely attributable

Conclusions

In summary we present the first comprehensive proteomic analysis of the widely studied Dnmt1 hypomorph colorectal cancer cells and identify redistribution of Dnmt1 and its interaction partner Beta-Catenin as well as the dysregulation of EMT related processes and signalling pathways related to the development of a cancer stem cell phenotype.
Feasibility of using a fully immersive virtual reality system for kinematic data collection
Authors: Spitzley Kate A. , Karduna Andrew R.
Published: February 2019

Commercially-available Virtual Reality (VR) systems have the potential to be effective tools for simultaneous visual manipulation and kinematic data collection. Previously, these systems have been integrated with research-grade motion capture systems to provide both functionalities; however, they are yet to be used as stand-alone systems for kinematic data collection. This study aimed to validate the HTC VIVE VR system for kinematic data collection by evaluating the accuracy of its position and orientation signals. The VIVE controller and tracker were each compared to a Polhemus Liberty magnetic tracking system sensor for angular and translational measurement error and signal drift. A sensor from each system was mounted to opposite ends of a rigid segment which was driven through fifty rotations and fifty translations. Mean angular errors for both the VIVE tracker and controller were below 0.4°. Mean translational error for both sensors was below 3 mm. Drift in the Liberty signal components was consistently lower than drift in VIVE components. However, all mean rotational drift measures were below 0.1° and all mean translational measures were below 0.35 mm. These data indicate that the HTC VIVE system may be a valid and reliable means of kinematic data collection. However, further investigation is necessary to determine the VIVE’s suitability for capturing extremely minute or high-volume movements.
Direct Visualization of Live Zebrafish Glycan via Single-step Metabolic Labeling with Fluorophore-tagged Nucleotide Sugars
Authors: Hong Senlian , Sahai-Hernandez Pankaj , Traver David , Wu Peng
Published: February 2019

Dynamic turnover of cell-surface glycans is involved in a myriad of biological events, making this process an attractive target for in vivo molecular imaging. The metabolic glycan labeling coupled with ‘bioorthogonal chemistry’ has paved the way for visulizing glycans in living organisms. However, a two-step labeling sequence is required, which is prone to tissue penetration difficulties of the imaging probes. Here, by exploring the substrate promiscuity of endogenous glycosyltransferases, we developed a single-step fluorescent glycan labeling strategy by using fluorophore-tagged analogs of nucleotide sugars directly. Injecting the fluorophore-tagged sialic acid and fucose into the yolk of zebrafish embryos at the one-cell stage enables a systematic imaging of sialylation and fucosylation in live zebrafish embryos at various developmental stages. From these studies, we obtained insights into the role of sialylated and fucosylated glycans in zebrafish hematopoiesis.