bluuebunny/crossref_metadata_2025 huggingface dataset:
Putative ligand binding sites of two functionally characterized bark beetle odorant receptors
Authors: Yuvaraj Jothi K. , Roberts Rebecca E. , Sonntag Yonathan , Hou Xiaoqing , Grosse-Wilde Ewald , Machara Aleš , Hansson Bill S. , Johanson Urban , Löfstedt Christer , Andersson Martin N.
Published: March 2020

Abstract

Bark beetle behavior is to a large extent mediated via olfaction. Targeting the odorant receptors (ORs) may thus provide avenues towards improved pest control during outbreaks. Such an approach requires information on the function of receptors and their interactions with ligands. Hence, we annotated 73 ORs from an antennal transcriptome of the spruce bark beetleIps typographusand report the functional characterization of two ORs (ItypOR46 and ItypOR49), which are selective for single enantiomers of the common bark beetle pheromone compounds ipsenol and ipsdienol, respectively. We use homology modeling and molecular docking to predict their binding sites. The importance of residues Tyr84 and Thr205 in ItypOR46 in the activation by ipsenol is experimentally supported, and hydrogen bonding appears key in pheromone binding. The biological significance of the characterized ORs positions them as prime targets for pest control and use in biosensors to detect bark beetle infestations.
Elevated temperatures impose transcriptional constraints on coffee genotypes and elicit intraspecific differences in thermoregulation
Authors: de Oliveira Raphael Ricon , Cherubino Ribeiro Thales Henrique , Cardon Carlos Henrique , Fedenia Lauren , Maia Vinicius Andrade , Ferrara Barbosa Barbara Castanheira , Caldeira Cecílio Frois , Klein Patricia E. , Chalfun-Junior Antonio
Published: March 2020

The projected impact of global warming on coffee production may require the heat-adapted genotypes in the next decades. To identify thermotolerance cellular strategies, we compared the effect of elevated temperature on two commercialCoffea arabicaL. genotypes exploring leaf physiology, transcriptome and carbohydrate/protein composition. Growth temperatures were 23/19°C (day/night), as optimal condition (OpT), and 30/26°C (day/night) as a possible warmer scenario (WaT). The cv. Acauã showed lower levels of leaf temperature under both conditions compared to cv. Catuaí, whereas slightly or no differences for other leaf physiological parameters. Therefore, to explore thermoregulatory pathways the leaf transcriptome was examined using RNAseq. Genotypes showed a marked number of differentially-expressed genes (DEGs) under OpT, however DEGs strongly decrease in both at WaT condition indicating a transcriptional constraint. DEGs responsive to WaT revealed shared and genotype-specific genes mostly related to carbohydrate metabolism. Under OpT, leaf starch content was greater in cv. Acauã although the levels of leaf starch, sucrose, and leaf protein decreased in both genotypes as WaT was imposed. These findings indicate that genotypes with a greater capacity to maintain carbohydrate homeostasis under temperature fluctuations could be more thermotolerant and which may be useful in breeding for a changing climate.

HIGHLIGHT

In response to warming, transcriptional differences decrease in coffee genotypes hampering breeding programs. Differences in gene expression and sugar levels confirm intraspecific variation associating thermotolerance to maintenance of energetic homeostasis.
User guide to the red blood cell model (RCM), a multiplatform JAVA-based model of human red blood cell homeostasis
Authors: Rogers Simon , Lew Virgilio L.
Published: March 2020

We introduce here a new multiplatform JAVA-based mathematical-computational model of RBC homeostasis for investigating the dynamics of changes in RBC homeostasis in health and disease. We provide a brief overview on the homeostasis of human RBCs and on the general biophysical principles guiding the modelling design. By way of a detailed tutorial we apply the model to investigate in depth the multiple effects associated with RBC dehydration induced by potassium permeabilization, a necessary preliminary for understanding the pathophysiology of a wide group of inherited haemolytic anaemias, a subject of intense current research and clinical interest. Using the red cell model (RCM), we design and run in silico representations of experimental protocols to study global RBC responses to calcium and potassium permeabilization covering a wide range of experimental, physiological and pathological conditions. Model outputs report the evolution in time of all the homeostatic variables in the system allowing, for the first time, a detailed and comprehensive account of the complex processes shaping global cell responses. Analysis of the results explains the mechanisms by which the entangled operation of all the RBC components link cell dehydration and protein crowding to cell acidification and to the generation of hypertonic, alkaline effluents. Open access to the RCM in a GitHub repository, together with the tutorial primed for a specific investigation pave the way for researchers and clinicians to apply the model on many different aspects of RBC physiology and pathology.
Integration of anatomy ontology data with protein-protein interaction networks improves the candidate gene prediction accuracy for anatomical entities
Authors: Fernando Pasan Chinthana , Mabee Paula M , Zeng Erliang
Published: March 2020

Background

Identification of genes responsible for anatomical entities is a major requirement in many fields including developmental biology, medicine, and agriculture. Current wet-lab techniques used for this purpose, such as gene knockout, are high in resource and time consumption. Protein-protein interaction (PPI) networks are frequently used to predict disease genes for humans and gene candidates for molecular functions, but they are rarely used to predict genes for anatomical entities. This is because PPI networks suffer from network quality issues, which can be a limitation for their usage in predicting candidate genes for anatomical entities. We developed an integrative framework to predict candidate genes for anatomical entities by combining existing experimental knowledge about gene-anatomy relationships with PPI networks using anatomy ontology annotations. We expected this integration to improve the quality of the PPI networks and be better optimized to predict candidate genes for anatomical entities. We used existing Uberon anatomy entity annotations for zebrafish and mouse genes to construct gene networks by calculating semantic similarity between the genes. These ‘anatomy-based gene networks’ are semantic networks, as they are constructed based on the Uberon anatomy ontology annotations that are obtained from the experimental data in the literature. We integrated these anatomy-based gene networks with mouse and zebrafish PPI networks retrieved from the STRING database, and we compared the performance of their network-based candidate gene predictions.

Results

According to candidate gene prediction performance evaluations tested under four different semantic similarity calculation methods (Lin, Resnik, Schlicker, and Wang), the integrated networks showed better receiver operating characteristic (ROC) and precision-recall curve performances than PPI networks for both zebrafish and mouse.

Conclusion

Integration of existing experimental knowledge about gene-anatomical entity relationships with PPI networksviaanatomy ontology improves the network quality, which makes them better optimized for predicting candidate genes for anatomical entities.
The circulatory physiopathology of human red blood cells investigated with a multiplatform model of cellular homeostasis. III. Senescence changes during the full circulatory lifespan
Authors: Rogers Simon , Lew Virgilio L.
Published: March 2020

Human red blood cells (RBCs) have a circulatory lifespan of about four months. Under constant oxidative and mechanical stress, but devoid of organelles and deprived of biosynthetic capacity for protein renewal, RBCs undergo substantial homeostatic changes, progressive densification followed by late density reversal among others, changes assumed to have been harnessed by evolution to sustain the rheological competence of the RBCs for as long as possible. The unknown mechanisms by which this is achieved are the subject of this investigation. Each RBC traverses capillaries between 1000 and 2000 times per day, roughly one transit per minute, a total of about 2•105transits during their lifespan. A dedicated Lifespan model of RBC homeostasis was developed as an extension of the RCM introduced in the first paper of this series to explore the cumulative patterns predicted for repetitive capillary transits over a standardized lifespan period of 120 days, using experimental data to constrain the parameter space. Capillary transits were simulated by periods of elevated cell/medium volume ratios and by transient deformation-induced permeability changes attributed to PIEZO1 channel mediation as outlined in the second paper of this series. The first unexpected finding was that quantal changes generated during single capillary transits cease accumulating after a few days and cannot account for the observed progressive densification of RBCs on their own, thus ruling out the quantal hypothesis. The second unexpected finding was that the documented patterns of RBC densification and late reversal could only be emulated by the implementation of a strict time-course of decay in the activities of the calcium and Na/K pumps, but only in addition to the quantal changes. These results showed that both quantal changes and pump-decay regimes were necessary to account for the documented lifespan pattern, neither sufficient on their own. They also suggested a strong selective component in the pump decay sequence. A third finding was that RBCs exposed to levels of calcium permeation above certain thresholds in the circulation could develop a pattern of late or early hyperdense collapse followed by delayed density reversal. When tested over much reduced lifespan periods the results emulated the known circulatory fate of irreversible sickle cells, the cell subpopulation responsible for vaso-occlusion and for most of the clinical manifestations of sickle cell disease. Analysis of the results provided an insightful new understanding of the mechanisms driving the changes in RBC homeostasis during circulatory aging in health and disease.
Structural basis for targeting human cancer antigen STEAP1 with antibodies
Authors: Oosterheert Wout , Gros Piet
Published: March 2020

Six-transmembrane epithelial antigen of the prostate (STEAP1) is an integral membrane protein that is highly upregulated on the cell surface of several human cancers, making it a promising therapeutic target. It shares sequence homology with three enzymes (STEAP2-4) that catalyze the NADPH-dependent reduction of iron(III). However, STEAP1 lacks an intracellular NADPH-binding domain and does not exhibit cellular ferric-reductase activity. Thus, both the molecular function of STEAP1 and its role in cancer progression remain elusive. Here, we present a ~3.0 Å cryo-electron microscopy structure of trimeric human STEAP1 bound to three Fab-fragments of the clinically employed antibody mAb120.545. STEAP1 adopts a reductase-like conformation and interacts with the Fabs through its extracellular helices. Enzymatic assays in human cells reveal that STEAP1 promotes iron(III) reduction when fused to the intracellular NADPH-binding domain of its family member STEAP4, implicating STEAP1 as a functional ferric reductase in STEAP hetero-trimers. Our work provides a foundation for deciphering the molecular mechanisms of STEAP1 and will be instrumental in the design of new therapeutic strategies to target STEAP1 in cancer.
Landscape drivers and effectiveness of pest control by insectivorous birds in a landscape-dominant woody crop
Authors: Martínez-Núñez Carlos , Rey Pedro J. , Manzaneda Antonio J. , García Daniel , Tarifa Rubén , Molina José L. , Salido Teresa
Published: March 2020

Avian-mediated pest control is a significant ecosystem service with important economic implications. However, there is an overall paucity of experimental information about how landscape simplification affect its current level. Information on pest control by birds is missing in some permanent agroecosystems of worldwide importance, like olive orchards, that dominate vast areas in the Mediterranean region.

We assess the effectiveness of insectivorous birds for controlling the two main pest insects in olive orchards and explore the effects of landscape complexity and distance to semi-natural patches on avian insectivore abundance and pest control. For this, we combine bird surveys with field experiments (branch exclusions and pest plasticine models) at the regional scale.

Landscape heterogeneity increased the abundance and richness of insectivorous birds, which were also more abundant and diverse in semi-natural patches, compared to the farm olive matrix. Experiments evidenced that pest control by birds (measured as attack rates to plasticine models and pest damage) in the studied olive orchards is negligible, while pests were overall abundant and pest damage was high on most farms. This raises alarms about the status of avian pest control in this agroecosystem.

Although landscape heterogeneity increased the abundance/richness of insectivorous birds, and favored some forest species, insectivorous bird abundance seems diluted in relation to prey availability in all landscapes. Thus, pest control by birds seems currently unsuccessful in olive orchards. Our results might be evidencing the loss of an ecosystem service due to a generalized massive decline of common and forest insectivorous birds.

Key message

Olive orchards dominate extensive areas causing important landscape simplification.

Insectivorous birds are more abundant in semi-natural patches within olive farms.

Field experiments show a low impact of birds on olive pests and damage.

Avian-mediated pest biocontrol seems diluted by limited suitable habitat for birds.

Agri-environmental measures should focus on increasing landscape complexity.
Loss of genetic variation in the two-locus multiallelic haploid model
Authors: Pontz Martin , Feldman Marcus W.
Published: March 2020

In the evolutionary biology literature, it is generally assumed that in deterministic haploid selection models, in the absence of variation-generating mechanisms such as mutation, no polymorphic equilibrium can be stable. However, results corroborating this claim are scarce and almost always depend upon additional assumptions. Using ideas from game theory, we establish a condition on the fitness parameters of haplotypes formed by two loci such that a monomorphism is a global attractor. Further, we show that no isolated equilibrium exists, at which an unequal number of alleles from two loci is present. Under the assumption of convergence of trajectories to equilirium points, we settle the two-locus three-allele case for a fitness scheme formally equivalent to the classical symmetric viability model.
The lupus autoantigen La is anXist-binding protein involved inXistfolding and cloud formation
Authors: Ha Norbert , Ding Nan , Hong Ru , Liu Rubing , Roca Xavier , Luo Yingyuan , Duan Xiaowei , Wang Xiao , Ni Peiling , Zhang Li-Feng , Chen Lingyi
Published: March 2020

Using the programmable RNA-sequence binding domain of the Pumilio protein, we FLAG-taggedXist(inactivatedXchromosomespecific transcript) in live cells. Affinity pulldown coupled to mass spectrometry was employed to identify a list of 138 candidateXist-binding proteins, from which, the lupus autoantigen La (encoding geneSsb) was validated as a protein functionally critical for X chromosome inactivation (XCI). Extensive XCI defects were detected inSsbknockdown cells, including chromatin compaction, death of female ES cells duringin vitrodifferentiation and chromosome-wide monoallelic gene expression pattern. Live-cell imaging ofXistRNA reveals the defining XCI defect:Xistcloud formation. La is a ubiquitous and versatile RNA-binding protein with RNA chaperone and RNA helicase activities. Functional dissection of La shows that the RNA chaperone domain and/or the ATP binding motif play critical roles in XCI. In mutant cells,Xisttranscripts are unstable and misfolded. These results show that La is critically involved in XCI, possibly as a protein regulating the in-cell structure ofXist.
Correlation of drug resistance with Single Nucleotide Variations through genome analysis and experimental validation in a multi-drug resistant clinical isolate ofM.tuberculosis
Authors: Bhattacharyya Kausik , Nemaysh Vishal , Joon Monika , Pratap Ramendra , Varma-Basil Mandira , Bose Mridula , Brahmachari Vani
Published: March 2020

Background

Genome sequencing and genetic polymorphism analysis of clinical isolates ofM.tuberculosisis carried out to gain further insight into molecular pathogenesis and host-pathogen interaction. Therefore the functional evaluation of the effect of single nucleotide variation (SNV) is essential. At the same time, the identification of invariant sequences unique toM.tuberculosiscontributes to infection detection by sensitive methods. In the present study, genome analysis is accompanied by evaluation of the functional implication of the SNVs in a MDR clinical isolate VPCI591.

Result

By sequencing and comparative analysis of VPCI591 genome with 1553 global clinical isolates ofM.tuberculosis, we identified 143 unique strain specific SNVs. A novel intergenic variation in VPCI591 in the putative promoter/regulatory region mapping betweenembC (Rv3793)andembA(Rv3794) genes was found to enhance the expression ofembAB, which correlates with the high resistance of the VPCI591 to ethambutol. Similarly, the unique combination of three genic SNVs in RNA polymerase β gene (rpoB) in VPCI591 was evaluated for its effect on rifampicin resistance through molecular docking analysis. The comparative genomics also showed that along with variations, there are genes that remain invariant. 173 such genes were identified in our analysis.

Conclusion

We have demonstrated that SNVs are not always benign and can also have functional effect. We show that variations bring about quantitative changes in transcription. Our results show the collective effect of SNVs on the structure of protein, impacting the interaction between the target protein and the drug molecule, withrpoBas an example.
Epigenetic Potential and DNA Methylation in an Ongoing House Sparrow (Passer domesticus) Range Expansion
Authors: Hanson Haley E. , Wang Chengqi , Schrey Aaron W. , Liebl Andrea L. , Jiang Rays H. Y. , Martin Lynn B.
Published: March 2020

During range expansions, epigenetic mechanisms may mediate phenotypic responses to environmental cues, enabling organisms to adjust to novel conditions at novel sites. Here, we predicted that the number of CpG sites within the genome, one form of epigenetic potential, would be important for success during range expansions because DNA methylation can modulate gene expression and hence facilitate adaptive plasticity. Previously, we found that this same form of epigenetic potential was higher in introduced compared to native populations of house sparrows (Passer domesticus) for two immune genes (Toll-like receptors2Aand4). Here, we took a reduced-representation sequencing approach (ddRadSeq and EpiRadSeq) to investigate how CpG site number, as well as resultant DNA methylation, varied across five sites in the ∼70 year-old Kenyan house sparrow range expansion. We found that the number of CpG sites increased towards the vanguard of the invasion, even when accounting for variation in genetic diversity among sites. This pattern was driven by more losses of CpG sites towards the core of the invasion (the initial site of introduction). Across all sequenced loci, DNA methylation decreased but became more variable towards the range-edge. However, in the subset CpG sites proximal to mutated CpG sites, DNA methylation increased and variation declined. These results indicate that epigenetic potential influenced the Kenyan house sparrow range expansion, likely by providing greater phenotypic plasticity which is genetically assimilated as populations adapt to local conditions. Similar mechanisms might underlie the successes and failures of other natural and anthropogenic range expansions.
Migration dynamics of an important rice pest: the brown planthopper (Nilaparvata lugens) across Asia – insights from population genomics
Authors: Hereward J. P. , Cai X.H. , Matias A. M. , Walter G. H. , Xu C. X. , Wang Y.
Published: March 2020

Brown planthoppers (Nilaparvata lugens) are the most serious insect pests of rice, one of the world’s most important staple crops. They reproduce year-round in the tropical parts of their distribution, but cannot overwinter in the temperate areas where they occur, and invade seasonally from elsewhere. Decades of research has not revealed their source unambiguously. We therefore sequenced the genomes of brown planthopper populations from across temperate and tropical parts of their distribution and show that the Indochinese peninsula is the major source of migration into temperate China. The Philippines, once considered a key source, is not significant, with little evidence for their migration into China. We find support for immigration from the west of China contributing to these regional dynamics. The lack of connectivity between the Philippines and mainland China explains the different evolution of Imidacloprid resistance in these populations. This study highlights the promise of whole genome sequence data to understand migration when gene flow is high – a situation that has been difficult to resolve using traditional genetic markers.
Plasmodiumoocysts respond with dormancy to crowding and nutritional stress
Authors: Habtewold Tibebu , Sharma Aayushi A. , Wyer Claudia A.S. , Masters Ellen K.G. , Windbichler Nikolai , Christophides George K.
Published: March 2020

Malaria parasites develop and grow as oocysts in the mosquito for several days before being able to infect another human. During this time, mosquitoes take regular bloodmeals to replenish their nutrient and energy reserves needed for flight and reproduction. We hypothesized that supplemental bloodmeals are critical for oocyst growth and that experimental infection protocols, typically involving a single bloodmeal, cause nutritional stress to developing oocysts. Therefore, enumerating oocysts independently of their growth and differentiation state may lead to erroneous conclusions regarding the efficacy of malaria transmission blocking interventions. We tested this hypothesis inAnopheles coluzziimosquitoes infected with human and rodent parasitesPlasmodium falciparumandPlasmodium berghei, respectively. We find that oocyst growth rates decrease at late developmental stages as infection intensities increase; an effect exacerbated at very high infection intensities. Oocyst growth and differentiation can be restored by supplemental bloodmeals even at high infection intensities. We show that high infection intensities as well as starvation conditions reduce RNA Polymerase III activity in oocysts unless supplemental bloodmeals are provided. Our data suggest that oocysts respond to crowding and nutritional stress by employing a dormancy-like strategy and urge development of alternative methods to assess the efficacy of transmission blocking interventions.
Contamination of Currency Notes with Kanamycin ResistantShigella flexneri
Authors: Al-Hajj Ebrahim Mohammed , Mohamed Malik Suliman , Abd Alfadil Noha A. , Altayb Hisham N. , Idris Abeer Babiker , El-Zaki Salah-Eldin , Hassan Mohamed A.
Published: March 2020

Shigella flexneriis the main causative agent of shigellosis commonly distributed in developing countries with high morbidity and mortality rates. This study aimed to examine the presence ofShigellaspecies in Sudanese currency notes using both traditional and molecular techniques. One hundred thirty five currency notes were collected and their contaminants were isolated and identified conventionally and genetically using 16S rRNA gene amplification and sequencing. Eight isolates were identified asShigellaspecies in different notes, and 3 of them were resistant to penicillin, kanamycin and nitrofurantoin. OneS. flexneriisolate has insertion mutation of guanine nucleotide at position 730 of life’s essential gene 16S rRNA which known evolutionarily to be stable gene. Banknotes are highly circulating items and therefore, appropriate measures such as regular replacement of the dirty notes with new papers are necessary to protect peoples from being infected with drug resistant pathogens.
Structure and function of virion RNA polymerase of crAss-like phage
Authors: Drobysheva Arina V. , Panafidina Sofia A. , Kolesnik Matvei V. , Klimuk Evgeny I. , Minakhin Leonid , Yakunina Maria V. , Borukhov Sergei , Nilsson Emelie , Holmfeldt Karin , Yutin Natalya , Makarova Kira S. , Koonin Eugene V. , Severinov Konstantin V. , Leiman Petr G. , Sokolova Maria L.
Published: March 2020

CrAss-like phages are a recently described family-level group of viruses that includes the most abundant virus in the human gut1,2. Genomes of all crAss-like phages encode a large virion-packaged protein2,3that contains a DFDxD sequence motif, which forms the catalytic site in cellular multisubunit RNA polymerases (RNAPs)4. UsingCellulophaga balticacrAss-like phage phi14:2 as a model system, we show that this protein is a novel DNA-dependent RNAP that is translocated into the host cell along with the phage DNA and transcribes early phage genes. We determined the crystal structure of this 2,180-residue enzyme in a self-inhibited, likely pre-virion-packaged state. This conformation is attained with the help of a Cleft-blocking domain that interacts with the active site motif and occupies the RNA-DNA hybrid binding grove. Structurally, phi14:2 RNAP is most similar to eukaryotic RNAPs involved in RNA interference5,6, although most of phi14:2 RNAP structure (nearly 1,600 residues) maps to a new region of protein folding space. Considering the structural similarity, we propose that eukaryal RNA interference polymerases take their origin in a phage, which parallels the emergence of the mitochondrial transcription apparatus7.
A neural m6A/YTHDF pathway is required for learning and memory inDrosophila
Authors: Kan Lijuan , Ott Stanislav , Joseph Brian , Park Eun Sil , Dai Crystal , Kleiner Ralph , Claridge-Chang Adam , Lai Eric C.
Published: March 2020

The roles of epitranscriptomic modifications in mRNA regulation have recently received substantial attention, with appreciation growing for their phenotypically selective impacts within the animal. We adoptedDrosophila melanogasteras a model system to study m6A, the most abundant internal modification of mRNA. Here, we report proteomic and functional analyses of fly m6A-binding proteins, confirming nuclear (YTHDC) and cytoplasmic (YTHDF) YTH domain proteins as the major m6A binders. Since all core m6A pathway mutants are viable, we assessedin vivorequirements of the m6A pathway in cognitive processes. Assays of short term memory revealed an age-dependent requirement of m6A writers working via YTHDF, but not YTHDC, comprising the first phenotypes assigned toDrosophilamutants of the cytoplasmic m6A reader. These factors promote memory via neural-autonomous activities, and are required in the mushroom body, the center for associative learning. To inform their basis, we mapped m6A from wild-type andmettl3null mutant heads, allowing robust discrimination of Mettl3-dependent m6A sites. In contrast to mammalian m6A, which is predominant in 3’ UTRs,Drosophilam6A is highly enriched in 5’ UTRs and occurs in an adenosine-rich context. Genomic analyses demonstrate thatDrosophilam6A does not directionally affect RNA stability, but is preferentially deposited on genes with low translational efficiency. However, functional tests indicate a role for m6A in translational activation, since we observe reduced nascent protein synthesis inmettl3-KOcells. Finally, we show that ectopic YTHDF can increase m6A target reporter output in an m6A-binding dependent manner, and that this activity is required forin vivoneural function of YTHDF in memory. Altogether, we provide the first tissue-specific m6A maps in this model organism and reveal selective behavioral and translational defects for m6A/YTHDF mutants.
Antibiotic-induced disturbances of the gut microbiota result in accelerated breast tumour growth via a mast cell-dependent pathway
Authors: Kirkup Benjamin M. , McKee Alastair M. , Madgwick Matthew , Price Christopher A , Dreger Sally A , Makin Kate A , Caim Shabhonam , Gall Gwenaelle Le , Paveley Jack , Leclaire Charlotte , Dalby Matthew , Alcon-Giner Cristina , Andrusaite Anna , Modica Martina Di , Triulzi Tiziana , Tagliabue Elda , Milling Simon WF , Weilbaecher Katherine N , Korcsmáros Tamas , Hall Lindsay J , Robinson Stephen D
Published: March 2020

The diverse community of commensal microbes that comprise the gut microbiota is known to play an integral role in human health, not least through its ability to regulate host immune responses and metabolic pathways. Alterations to the homeostasis of this community, including through the use of broad-spectrum antibiotics, have already been associated with the progression of several cancers, namely melanoma and liver. The aggressive nature of breast cancer (BrCa), largely due to its ability to metastasize early, has ranked the disease with the second highest mortality rate of all cancers globally. Yet the body of research into the complex relationship between the microbiota and BrCa is still limited. This study found that a depletion of the microbiota, through the administration of antibiotics, significantly increased the rate of primary tumour progression in mouse BrCa models. We show that antibiotic-induced microbiota disturbances lead to changes in behaviour of a relatively obscure tumour-immune cell population: mast cells. We observed increases in tumour stroma-associated mast cells in antibiotic treated animals. Moreover, inhibition of mast cell degranulation, via cromolyn, slowed tumour progression in antibiotic treated animals but not in control animals. Thus, it appears that a perturbed microbiota drives stroma-associated mast cell recruitment and activation, which in turn promotes primary tumour growth through an as yet unknown mechanism.

One Sentence Summary:We show that breast cancer progression is accelerated through a unique/novel immune response involving mast cells as a result of an antibiotic induced perturbation of the gut microbiota in a mouse model.
Meta-transcriptomic analysis of virus diversity in urban wild birds with paretic disease
Authors: Chang Wei-Shan , Eden John-Sebastian , Hall Jane , Shi Mang , Rose Karrie , Holmes Edward C.
Published: March 2020

Wild birds are major natural reservoirs and potential dispersers of a variety of infectious diseases. As such, it is important to determine the diversity of viruses they carry and use this information to help understand the potential risks of spill-over to humans, domestic animals, and other wildlife. We investigated the potential viral causes of paresis in long-standing, but undiagnosed disease syndromes in wild Australian birds. RNA from diseased birds was extracted and pooled based on tissue type, host species and clinical manifestation for metagenomic sequencing. Using a bulk and unbiased meta-transcriptomic approach, combined with careful clinical investigation and histopathology, we identified a number of novel viruses from the familiesAstroviridae, Picornaviridae, Polyomaviridae, Paramyxoviridae, Parvoviridae, Flaviviridae,andCircoviridaein common urban wild birds including Australian magpies, magpie lark, pied currawongs, Australian ravens, and rainbow lorikeets. In each case the presence of the virus was confirmed by RT-PCR. These data revealed a number of candidate viral pathogens that may contribute to coronary, skeletal muscle, vascular and neuropathology in birds of theCorvidaeandArtamidaefamilies, and neuropathology in members of thePsittaculidae. The existence of such a diverse virome in urban avian species highlights the importance and challenges in elucidating the etiology and ecology of wildlife pathogens in urban environments. This information will be increasingly important for managing disease risks and conducting surveillance for potential viral threats to wildlife, livestock and human health. More broadly, our work shows how meta-transcriptomics brings a new utility to pathogen discovery in wildlife diseases.

Importance

Wildlife naturally harbor a diverse array of infectious microorganisms and can be a source of novel diseases in domestic animals and human populations. Using unbiased RNA sequencing we identified highly diverse viruses in native birds in Australian urban environments presenting with paresis. This investigation included the clinical investigation and description of poorly understood recurring syndromes of unknown etiology: clenched claw syndrome, and black and white bird disease. As well as identifying a range of potentially disease-causing viral pathogens, this study describes methods that can effectively and efficiently characterize emergent disease syndromes in free ranging wildlife, and promotes further surveillance for specific potential pathogens of potential conservation and zoonotic concern.
A causal role for pulvinar in coordinating task independent cortico-cortical interactions
Authors: Eradath Manoj K. , Pinsk Mark A. , Kastner Sabine
Published: March 2020

Pulvinar is the largest nucleus in the primate thalamus and has topographically organized connections with multiple cortical areas, thereby forming extensive cortico-pulvino-cortical input-output loops. Neurophysiological studies have provided evidence for a role of these transthalamic pathways in regulating information transmission between cortical areas. However, a causal role of pulvinar in regulating cortico-cortical interactions has not yet been demonstrated. In particular, it is not known whether pulvinar’s influences on cortical networks are task-dependent or reflect more basic large-scale network properties that maintain functional connectivity across a network regardless of active task demands. In the current study, under a passive viewing condition, we conducted simultaneous electrophysiological recordings from interconnected ventral (area V4) and dorsal (LIP) nodes of the macaque visual system while reversibly inactivating the dorsal part of lateral pulvinar (dPL), which shares common anatomical connectivity with V4 and LIP. Our goal was to probe a causal role of pulvinar in regulating cortico-cortical interactions in the absence of any active task demands. Our results show a significant reduction in local field potential phase coherence between LIP and V4 in low frequencies (4-15 Hz) following muscimol -a potent GABAAagonist -injection into dPL. At the local level, no significant changes in firing rates or LFP power were observed in LIP or in V4 following dPL inactivation. These results indicate a causal role for pulvinar in synchronizing neural activity between interconnected cortical nodes of a large-scale network, even in the absence of an active task state.

Significance Statement

Pulvinar, the largest nucleus of the primate thalamus, has been implicated in several cognitive functions. The extensive cortico-pulvino-cortical loops formed by pulvinar are suggested to be regulating information transmission between interconnected cortical areas. However, a causal evidence for pulvinar’s role in cortico-cortical interactions in the absence of active task demands is not yet clear. We conducted simultaneous recordings from nodes of macaque visual system (areas V4 and LIP) while inactivating the dorsal part of the lateral pulvinar (dPL) under a passive viewing condition. Our results show a significant reduction in local field phase coherence between LIP and V4 in low frequencies (4-15 Hz) following inactivation of dPL, thus providing evidence for a causal role of pulvinar in regulating cortico-cortical interactions even in the absence of an active task state.
ProGen: Language Modeling for Protein Generation
Authors: Madani Ali , McCann Bryan , Naik Nikhil , Keskar Nitish Shirish , Anand Namrata , Eguchi Raphael R. , Huang Po-Ssu , Socher Richard
Published: March 2020

Generative modeling for protein engineering is key to solving fundamental problems in synthetic biology, medicine, and material science. We pose protein engineering as an unsupervised sequence generation problem in order to leverage the exponentially growing set of proteins that lack costly, structural annotations. We train a 1.2B-parameter language model, ProGen, on ∼280M protein sequences conditioned on taxonomic and keyword tags such as molecular function and cellular component. This provides ProGen with an unprecedented range of evolutionary sequence diversity and allows it to generate with fine-grained control as demonstrated by metrics based on primary sequence similarity, secondary structure accuracy, and conformational energy.
mbImpute: an accurate and robust imputation method for microbiome data
Authors: Jiang Ruochen , Li Wei Vivian , Li Jingyi Jessica
Published: March 2020

Microbiome studies have gained increased attention since many discoveries revealed connections between human microbiome compositions and diseases. A critical challenge in microbiome research is that excess non-biological zeros distort taxon abundances, complicate data analysis, and jeopardize the reliability of scientific discoveries. To address this issue, we propose the first imputation method, mbImpute, to identify and recover likely non-biological zeros by borrowing information jointly from similar samples, similar taxa, and optional metadata including sample covariates and taxon phylogeny. Comprehensive simulations verified that mbImpute achieved better imputation accuracy under multiple measures than five state-of-the-art imputation methods designed for non-microbiome data. In real data applications, we demonstrate that mbImpute improved the power and reproducibility of identifying disease-related taxa from microbiome data of type 2 diabetes and colorectal cancer.
Effects of attapulgite on the worn surface and fretting wear resistance property of UHMWPE composites
Authors: Meng Zhaojie , Wang Yunxia , Xin Xiaocui , Liu Hao , Yan Yunfeng , Yan Fengyuan
Published: March 2020

Purpose

The purpose of this study is to examine the fretting wear property of ultra-high molecular weight polyethylene (UHMWPE)-based composites reinforced by different content of attapulgite.

Design/methodology/approach

A series of composites were prepared by a hot-pressing method. Fretting tests were carried out using an SRV-IV oscillating reciprocating friction wear tester with a load of 10 N and a frequency of 100 Hz. The morphology of the fracture structure and the worn surface was observed by field-emission scanning electron microscopy, X-ray diffraction and a non-contact three dimensional surface profiler.

Findings

With the addition of attapulgite, the microstructure of the composites become more regular, and their heat resistance improved. Furthermore, the friction coefficient and the specific wear rate of the composites with lower filler content reduced compared with that of neat UHMWPE, and the optimum filler content is 1 per cent.

Originality/value

The study investigated the fretting resistance mechanism of the attapulgite in the UHMWPE matrix. The results could help to provide some experimental evidence for the broader application of silicates on the fretting wear resistance of polymers.

Peer review

The peer review history for this article is available at: https://publons.com/publon/10.1108/ILT-10-2019-0420/
Demographics, natural history and treatment outcomes of non‐molar gestational choriocarcinoma: a UK population study
Authors: Savage P , Winter M , Parker V , Harding V , Sita‐Lumsden A , Fisher RA , Harvey R , Unsworth N , Sarwar N , Short D , Aguiar X , Tidy J , Hancock B , Coleman R , Seckl MJ
Published: March 2020

Objective

To investigate the demographics, natural history and treatment outcomes of non‐molar gestational choriocarcinoma.

Design

A retrospective national population‐based study.

Setting

UK 1995–2015.

Population

A total of 234 women with a diagnosis of gestational choriocarcinoma, in the absence of a prior molar pregnancy, managed at the UKs two gestational trophoblast centres in London and Sheffield.

Methods

Retrospective review of the patient’s demographic and clinical data. Comparison with contemporary UK birth and pregnancy statistics.

Main outcomes

Incidence statistics for non‐molar choriocarcinoma across the maternal age groups. Cure rates for patients by FIGO prognostic score group.

Results

Over the 21‐year study period, there were 234 cases of non‐molar gestational choriocarcinoma, giving an incidence of 1:66 775 relative to live births and 1:84 226 to viable pregnancies. For women aged under 20, the incidence relative to viable pregnancies was 1:223 494, for ages 30–34, 1:80 227, and for ages 40–45, 1:41 718. Treatment outcomes indicated an overall 94.4% cure rate. Divided by FIGO prognostic groups, the cure rates were low‐risk group 100%, high‐risk group 96% and ultra‐high‐risk group 80.5%.

Conclusions

Non‐molar gestational choriocarcinoma is a very rare diagnosis with little prior detailed information on the demographics and natural history. The data in this study give age‐related incidence data based on a large national population study. The results also demonstrated the widely varying natural history of this rare malignancy and the marked correlation of disease incidence with rising maternal age.

Tweetable abstract

National gestational choriocarcinoma database indicates a close association between increasing maternal age and incidence.
Long‐term consequences of being placed in disciplinary segregation†
Authors: Wildeman Christopher , Andersen Lars Højsgaard
Published: March 2020

Being placed in restrictive housing is considered one of the most devastating experiences a human can endure, yet a scant amount of research has been conducted to test how this experience affects core indicators of prisoner reentry such as employment and recidivism. In this article, we use Danish registry data, which allow for us to link penal conditions to postrelease outcomes, to show how the reentry outcomes of individuals placed in disciplinary segregation, which is placement in restrictive housing because of disciplinary infractions, compare with those sanctioned for in‐prison offenses but not placed in segregation. The results from matched difference‐in‐differences analyses show that Danish inmates placed in disciplinary segregation experience larger drops in employment and larger increases in the risk of being convicted of a new crime in the 3 years after release from a correctional facility than do Danish inmates who were sanctioned for a serious offense but not placed in disciplinary segregation as a result. Because being placed in disciplinary segregation, and restrictive housing more broadly, is so common, these results indicate that restrictive housing placement may be a key moderator of the effects of incarceration that merits more attention from criminologists, provided the associations shown here represent causal effects and generalize.
Combined non‐intubated anaesthesia and paravertebral nerve block in comparison with intubated anaesthesia in children undergoing video‐assisted thoracic surgery
Authors: Wei Wei , Fan Yanting , Liu Wei , Zhao Tianyun , Tian Hang , Xu Yingyi , Tan Yonghong , Song Xingrong , Ma Daqing
Published: March 2020

Background

This study is to investigate if non‐intubated anaesthesia combined with paravertebral nerve block (PVNB) can enhance recovery in children undergoing video‐assisted thoracic surgery (VATS).

Methods

A randomized controlled trial including 60 patients aged 3 to 8 years old who underwent elective VATS was performed. They were randomly assigned to receive non‐intubated anaesthesia combined with PVNB or general anaesthesia with tracheal intubation (1:1 ratio). The primary outcome was the length of postoperative in‐hospital stay. The secondary outcomes included emergence time, the incidence of emergence delirium, time to first feeding, time to first out‐of‐bed activity, pain score and in‐hospital complications.

Results

The non‐intubated group had shorter postoperative in‐hospital stay than the control group (4 days [IQR, 4‐6] vs 5 days [IQR, 5‐8], 95% CI 0‐2; P = .013). When compared to the control group, the incidence of emergence delirium (odds ratio [OR] 3.39, 95% CI 1.01‐11.41; P = .043), emergence time, duration in the PACU, time to first eating food, first out‐of‐bed activity, pain score and consumption of sufentanil (at 6 and 12 hours after surgery) were decreased in the intervention group. In contrast, the incidence of airway complications was higher in the control than the intervention group (27.6% vs 6.9%, P = .037). There was no statistical significance in the occurrence of PONV, pneumothorax and other complications between the two groups.

Conclusions

Non‐intubated anaesthesia combined with PVNB enhances recovery in paediatric patients for video‐assisted thoracic surgery although further multi‐centre study is needed.
Is R(+)‐Baclofen the best option for the future of Baclofen in alcohol dependence pharmacotherapy? Insights from the preclinical side
Authors: Echeverry‐Alzate Victor , Jeanblanc Jérôme , Sauton Pierre , Bloch Vanessa , Labat Laurence , Soichot Marion , Vorspan Florence , Naassila Mickael
Published: March 2020

For several decades, studies conducted to evaluate the efficacy of RS(±)‐Baclofen in the treatment of alcohol dependence yielded contrasting results. Human and animal studies recently questioned the use of the racemic drug in patients since a potential important role of the different enantiomers has been revealed with an efficacy thought to reside with the active R(+)‐enantiomer. Here we conducted experiments in the postdependent rat model of alcohol dependence to compare the efficacy of R(+)‐Baclofen or S(−)‐Baclofen to that of RS(±)‐Baclofen on ethanol intake, seeking, and relapse. R(+)‐Baclofen was more effective than RS(±)‐Baclofen in reducing ethanol intake and seeking during acute withdrawal and during relapse after abstinence. We also used an original population approach in order to identify drug responders. We found a significant proportion of responders to S(−)‐Baclofen and RS(±)‐Baclofen, displaying an increase in ethanol intake, and this increasing effect on alcohol intake was not seen in the R(+)‐Baclofen group. At an intermediate dose of R(+)‐Baclofen, devoid of any motor side effects, we identified a very large proportion of responders (75%) with a large decrease in ethanol intake (90% decrease). Finally, the response to RS(±)‐Baclofen on ethanol intake was correlated to plasma level of Baclofen. R(+)‐Baclofen and RS(±)‐Baclofen were effective in reducing sucrose intake. Our study has important clinical implication since it suggests that the wide variability in the therapeutic responses of patients to RS(±)‐Baclofen may come from the sensitivity to the R(+)‐Baclofen but also to the one of the S(−)‐Baclofen that can promote an increase in ethanol intake.