bluuebunny/crossref_metadata_2025 huggingface dataset:
TrackSig: reconstructing evolutionary trajectories of mutations in cancer
Authors: Rubanova Yulia , Shi Ruian , Harrigan Caitlin F , Li Roujia , Wintersinger Jeff , Sahin Nil , Deshwar Amit , Morris Quaid ,   PCAWG Evolution and Heterogeneity Working Group,   PCAWG network
Published: February 2018

We present a new method, TrackSig, to estimate the evolutionary trajectories of signatures of different somatic mutational processes from DNA sequencing data from a single, bulk tumour sample. TrackSig uses probability distributions over mutation types, called mutational signatures, to represent different mutational processes and detects the changes in the signature activity using an optimal segmentation algorithm that groups somatic mutations based on their estimated cancer cellular fraction (CCF) and their mutation type (e.g. CAG->CTG). We use two different simulation frameworks to assess both TrackSig’s reconstruction accuracy and its robustness to violations of its assumptions, as well as to compare it to a baseline approach. We find 2-4% median error in reconstructing the signature activities on simulations with varying difficulty with one to three subclones at an average depth of 30x. The size and the direction of the activity change is consistent in 83% and 95% of cases respectively. There were an average of 0.02 missed and 0.12 false positive subclones per sample. In our simulations, grouping mutations by mutation type (TrackSig), rather than by clustering CCF (baseline strategy), performs better at estimating signature activities and at identifying subclonal populations in the complex scenarios like branching, CNA gain, violation of infinite site assumption, and the inclusion of neutrally evolving mutations. TrackSig is open source software, freely available at https://github.com/morrislab/TrackSig.
Sexual isolation with and without ecological isolation in marine isopodsJ. albifronsandJ. praehirsuta
Authors: Ribardière Ambre , Pabion Elsa , Coudret Jérôme , Daguin-Thiébaut Claire , Houbin Céline , Loisel Stéphane , Henry Sébastien , Broquet Thomas
Published: February 2018

Sexual barriers associated with mate choice are nearly always found to be associated with some level of ecological isolation between species. The independence and relative strength of sexual isolation are thus difficult to assess. Here we take advantage of a pair of isopod species (Jaera albifronsandJ. praehirsuta) that show sexual isolation and coexist in populations where they share the same microhabitat or not (i.e. without or with ecological isolation). Using no-choice trials and a free-choice experimental population, we estimated the strength of sexual isolation betweenJ. albifronsandJ. praehirsutaindividuals originating from these different ecological contexts. We found that sexual isolation is strong in presence and absence of ecological isolation, but that it is asymmetric and fails to prevent gene flow entirely. First-generation post-zygotic barriers were low, and there was no sexual isolation withinJ. praehirsutaacross habitats. TheJ. albifrons/J. praehirsutaspecies pair thus provides an example where the role of sexual isolation as a barrier to gene flow i) does not depend upon current ecological isolation, ii) seems to have evolved independently of local ecological conditions, but iii) is insufficient to complete speciation entirely on its own.
Scopoletin Augments DJ1/Nrf2 Signalling and Prevents Protein Aggregation in Parkinson’s disease
Authors: Kishore Kumar S Narasimhan , Deepthy Jayakumar , Prema Velusamy , Ashokkumar Srinivasan , Thangarajeswari Mohan , Bhavani Ravi Divya , Saraswathi Uthamaraman , Yogesh Kanna Sathyamoorthy , Rajasekaran Namakal S. , Kalaiselvi Periandavan
Published: February 2018

Given the role of oxidative stress in PD pathogenesis and off-target side effects of currently available drugs, several natural phytochemicals seems to be promising in the management of PD. Here, we tested the hypothesis that scopoletin, an active principle obtained from Morinda citrifolia (MC), efficiently quenches oxidative stress through DJ-1/Nrf2 signalling and ameliorates rotenone-induced PD. Despite reducing the oxidative stress, administration of MC extract (MCE) has lessened the protein aggregation as evident from decreased levels of nitrotyrosine and α-Synuclein. In vitro studies revealed that scopoletin lessened rotenone-induced apoptosis in SH-SY5Y cells through preventing oxidative injury. Particularly, scopoletin markedly up-regulated DJ-1, which then promoted the nuclear translocation of Nrf2 and transactivation of antioxidant genes. Furthermore, we found that scopoletin prevent the nuclear exportation of Nrf2 by reducing the levels of Keap1 and thereby enhancing the neuronal defence system. Overall, our findings suggest that scopoletin acts through DJ-1 mediated Nrf2 signalling to protect the brain from rotenone-induced oxidative stress and PD. Thus, we postulate that scopoletin could be a potential drug to treat PD.
In situ administration of cytokine combinations induces tumor regression
Authors: Zhang Jinyu , Jiang Haochen , Zhang Yunhai
Published: February 2018

Recent advances in cancer immunotherapy suggest a possibility of harnessing the immune system to defeat malignant tumors, but complex immunosuppressive microenvironment confined the therapeutic benefits to a minority of patients with solid tumors. Here we constructed a lentivector based inducible system to evaluate the therapeutic effect of cytokines in established tumors. Doxycycline (Dox) induced local expression of cytokine combinations exhibited strong synergistic effect, leading to complete regression of tumors. Notably, IL12+GMCSF+IL2 expression induced eradication of tumors in all mice tolerated with this treatment, including those bearing large tumors of ~15mm in diameter, and generated an intensive systemic antitumor immunity. Other combinations with similar immune regulatory roles also induced tumor elimination in a majority of mice. Moreover, intratumoral injection of chitosan/IL12+GMCSF+IL2 solution induced complete response in all tested syngeneic tumor models, regardless of various tumor immunograms. These results provide a versatile method for the immunotherapy of intractable malignant neoplasm.
Individual- and population-level drivers of consistent foraging success across environments
Authors: Snijders Lysanne , Kurvers Ralf H. J. M. , Krause Stefan , Ramnarine Indar W. , Krause Jens
Published: February 2018

Individual foraging is under strong natural selection. Yet, whether individuals differ consistently in their foraging success across environments, and which individual and population-level traits might drive such differences, is largely unknown. We addressed this question in a field experiment, conducting over 1,100 foraging trials with nine subpopulations of guppies,Poecilia reticulata, translocating them across environments in the wild. A-priori, we determined the individual social phenotypes. We show that individuals consistently differed in reaching food, but not control, patches across environments. Social individuals reached more food patches than less social ones and males reached more food patches than females. Overall, individuals were, however, more likely to join females at patches than males, which explains why individuals in subpopulations with relatively more females reached, on average, more food patches. Our results provide rare evidence for individual differences in foraging success across environments, driven by individual and population level (sex ratio) traits.
High carnivore population density highlights the conservation value of industrialised sites
Authors: Loock Daan J. E. , Williams Samual T. , Emslie Kevin W. , Matthews Wayne S. , Swanepoel Lourens H.
Published: February 2018

As the environment becomes increasingly altered by human development, the importance of understanding the ways in which wildlife interact with modified landscapes is becoming clear. Areas such as industrial sites are sometimes presumed to have little conservation value, but many of these sites have areas of less disturbed habitats around their core infrastructure, which could provide ideal conditions to support some species, such as mesocarnivores. We conducted the first assessments of the density of serval (Leptailurus serval) at the Secunda Synfuels Operations plant, South Africa. We ran three camera trap surveys to estimate serval density using a spatially explicit capture recapture framework. Servals occurred at densities of 76.20-101.21 animals per 100 km2, which are the highest recorded densities for this species, presumably due to high abundance of prey and the absence of persecution and/or competitor species. Our findings highlight the significant conservation potential of industrialised sites, and we suggest that such sites could help contribute towards meeting conservation goals.
Taxonomic Profiling and Populational Patterns of Bacterial Bile Salt Hydrolase (BSH) Genes on Worldwide Human Gut Microbiome
Authors: Song Ziwei , Cai Yuanyuan , Wang Xue , Lin Xiaoxuan , Cui Yingyun , Shang Jing , Jin Liang , Li Jing
Published: February 2018

Bile salt hydrolase (BSH) in gut bacteria can hydrolyze conjugated bile salts to unconjugated bile acids and amino acids. Thereby play a crucially important role in host health by reducing serum cholesterol levels, preserving bile acids balance and regulating various metabolism as signaling molecules. Here we present the taxonomic identification of BSHs in human microbiota and elucidate the abundance and activity differences of various bacterial BSHs among 11 different populations. For the first time, we have revealed BSH are distributed in 154 intestinal bacterial strains within 33 genera in human microbiota. However, these BSHs present obviously differentiation for the sequence identity being from 28.6% to 100%, and the 32.7% bacteria strains having more than one paralogs of BSHs with dissimilarity. Therefore, we reclassified the BSHs from the different genera into 6 phylotypes basing on their phylogenetic tree, and demonstrate the significant abundance patterns of BSH phylotypes among different populations. From the enzyme activity comparison, the representative sequence of BSH-T3 was shown highest enzyme activity in 6 phylotypes. Meanwhile, BSH-T3 sequences which all distributed inLactobacillusshow highest abundance in Chinese and Austrian. The information illustrated by this study is useful for investigating the population differences of bile acid metabolism related diseases, and further giving a new suggestion on selection of probiotics or development of pharmaceutical proteins based upon the activity of BSH phylotypes to regulate host metabolism and maintain fitness.
Naked mole-rat brain neurons are resistant to acid-induced cell death
Authors: Husson Zoé , Smith Ewan St John
Published: February 2018

Regulation of brain pH is a critical homeostatic process and changes in brain pH modulate various ion channels and receptors and thus neuronal excitability. Tissue acidosis, resulting from hypoxia or hypercapnia, can activate various proteins and ion channels, among which acid-sensing ion channels (ASICs) a family of primarily Na+permeable ion channels, which alongside classical excitotoxicity causes neuronal death. Naked mole-rats (NMRs,Heterocephalus glaber) are long-lived, fossorial, eusocial rodents that display remarkable behavioral/cellular hypoxia and hypercapnia resistance. In the central nervous system, ASIC subunit expression is similar between mouse and NMR with the exception of much lower expression of ASIC4 throughout the NMR brain. However, ASIC function and neuronal sensitivity to sustained acidosis has not been examined in the NMR brain. Here, we show with whole-cell patch-clamp electrophysiology of cultured NMR and mouse cortical and hippocampal neurons that NMR neurons have smaller voltage-gated Na+channel currents and more hyperpolarized resting membrane potentials. We further demonstrate that acid-mediated currents in NMR neurons are of smaller magnitude than in mouse, and that all currents in both species are fully blocked by the ASIC antagonist benzamil. We further demonstrate that NMR neurons show greater resistance to acid-induced cell death than mouse neurons. In summary, NMR neurons show significant cellular resistance to acidotoxicity compared to mouse neurons, contributing factors likely to be smaller ASIC-mediated currents and reduced NaV activity.

Abbreviations

ASIC, acid-sensing ion channel; CNS, central nervous system; DRG, dorsal root ganglion; NaV, voltage-gated Na+channel; NMR, naked mole-rat; TTX, tetrodotoxin
The interplay of synaptic plasticity and scaling enables self-organized formation and allocation of multiple memory representations
Authors: Maria Auth Johannes , Nachstedt Timo , Tetzlaff Christian
Published: February 2018

It is commonly assumed that memories about experienced stimuli are represented by groups of highly interconnected neurons called cell assemblies. This requires allocating and storing information in the neural circuitry, which happens through synaptic weight adaptation. It remains, however, largely unknown how memory allocation and storage can be achieved and coordinated to allow for a faithful representation of multiple memories without disruptive interference between them. In this theoretical study, we show that the interplay between conventional synaptic plasticity and homeostatic synaptic scaling organizes synaptic weight adaptations such that a new stimulus forms a new memory and where different stimuli are assigned to distinct cell assemblies. The resulting dynamics can reproduce experimental in-vivo data, focusing on how diverse factors as neuronal excitability and network connectivity, influence memory formation. Thus, the here presented model suggests that a few fundamental synaptic mechanisms may suffice to implement memory allocation and storage in neural circuitry.
The role of Aβ circRNA in Alzheimer’s disease: alternative mechanism of Aβ biogenesis from Aβ circRNA translation
Authors: Mo Dingding , Li Xinping , Raabe Carsten A. , Rozhdestvensky Timofey S. , Skryabin Boris V. , Brosius Juergen
Published: February 2018

Alzheimer’s disease (AD) is an age-related detrimental dementia. Amyloid beta peptides (Aβ) play a crucial role in the pathology of AD. In familial AD, Aβ is generated from the full-length amyloid precursor protein (APP) via dysregulated proteolytic processing. However, Aβ biogenesis in case of sporadic AD remains so far elusive. circRNAs are a class of transcripts, which are preferentially expressed in brain. Here, we identified a circRNA (circAβ-a) derived from the Aβ-coding region of the APP gene. circAβ-a is expressed in brains of AD and nondementia controls. With the aid of our recently established approach for analysis of circRNA functions, we demonstrated that circAβ-a is efficiently translated into a novel Aβ-related Aβ175 protein in living cells. Importantly, Aβ175 was further processed to Aβ peptides, the hallmark of AD. In summary, our analysis revealed alternative route of Aβ biogenesis. circAβ-a and its corresponding protein might represent novel therapeutic targets for AD treatment.
Molecular basis of mitotic decline during human aging
Authors: Macedo Joana Catarina , Vaz Sara , Bakker Bjorn , Ribeiro Rui , Bakker Petra , Escandell Jose Miguel , Ferreira Miguel Godinho , Medema René , Foijer Floris , Logarinho Elsa
Published: February 2018

Aneuploidy, an abnormal chromosome number, has been linked to aging and age-associated diseases, but the underlying molecular mechanisms remain unknown. Supported by direct live-cell imaging of young, middle-aged and old-aged primary human dermal fibroblasts, we found that aneuploidy increases with aging due to general dysfunction of the mitotic machinery. Increased chromosome segregation defects in elderly mitotic cells correlated with an early senescence-associated secretory phenotype (SASP) and repression of Forkhead box M1 (FoxM1), the transcription factor that drives expression of most G2/M genes. By restoring FoxM1 levels in elderly and Hutchison-Gilford Progeria Syndrome fibroblasts we prevented aneuploidy and, importantly, ameliorated cellular phenotypes associated with aging. Moreover, senescent fibroblasts isolated from elderly donors’ cultures were mostly aneuploid, suggesting that aneuploidy is a key player in the progression into full senescence phenotypes. Based on this feedback loop between cellular aging and aneuploidy, we propose modulation of mitotic efficiency through FoxM1 as a potential strategy against aging and progeria syndromes.
The subesophageal ganglion modulates locust inter-leg sensory-motor interactions via contralateral pathways
Authors: Knebel Daniel , Wörner Johanna , Rillich Jan , Nadler Leonard , Ayali Amir , Couzin-Fuchs Einat
Published: February 2018

The neural control of insect locomotion is distributed among various body segments. Local pattern-generating circuits at the thoracic ganglia interact with incoming sensory signals and central descending commands from the head ganglia. The evidence from different insect preparations suggests that the subesophageal ganglion (SEG) may play an important role in locomotion-related tasks. In a previous study, we demonstrated that the locust SEG modulates the coupling pattern between segmental leg CPGs in the absence of sensory feedback. Here, we investigated its role in processing and transmitting sensory information to the leg motor centers, and mapped the major related neural pathways. Specifically, the intra- and inter-segmental transfer of leg-feedback were studied by simultaneously monitoring motor responses and descending signals from the SEG. Our findings reveal a crucial role of the SEG in the transfer of intersegmental, but not intrasegmental, signals. Additional lesion experiments, in which the intersegmental connectives were cut at different locations, together with double nerve staining, indicated that sensory signals are mainly transferred to the SEG via the connective contralateral to the stimulated leg. We therefore suggest that, similar to data reported for vertebrates, insect leg sensory-motor loops comprise contralateral ascending pathways to the head and ipsilateral descending ones.
Using movement data to estimate contact rates in a simulated environmentally-transmitted disease system
Authors: Dougherty Eric R. , Seidel Dana P. , Carlson Colin J. , Getz Wayne M.
Published: February 2018

Agent-based models have become important tools in ecology, particularly in the study of infectious disease dynamics. Simulations of near-continuous movement paths guided by empirical data offer new avenues of investigation into disease transmission. Here, we simulate the spatiotemporal transmission dynamics of anthrax, the acute disease caused by the bacteriumBacillus anthracis, a pathogen transmitted primarily via environmental reservoirs. We explore how calculations of the probabilities of contact between a host and infectious reservoirs are affected by the scale and method of analysis. At both the landscape and individual scales, empirical movement tracks offer previously unattainable estimates of impacts of movement decisions on contact rate metrics. However, the analytical method selected for the calculation of the probability of contact has notable impacts on the resulting estimates, with convex polygons virtually canceling out variation, and unions of local convex hulls (LoCoH methods) and space-time prisms reflecting reasonable variation, but differing in the magnitude of their estimates. The explicit consideration of behavioral states along movement pathways also impacts evaluations of exposure risk, though its effects differ across methods of analysis. Ultimately, simulations demonstrate that the incorporation of movement data into pathogen transmission analyses helps clarify the role of movement processes underlying the observed dynamics of infectious disease.
Baldspot/ELOVL6 is a conserved modifier of disease and the ER stress response ELOVL6 modifies ER stress
Authors: Palu Rebecca A. S. , Chow Clement Y.
Published: February 2018

Endoplasmic reticulum (ER) stress is an important modifier of human disease. Genetic variation in genes involved in the ER stress response has been linked to inter-individual differences in this response. However, the mechanisms and pathways by which genetic modifiers are acting on the ER stress response remain unclear. In this study, we characterize the role of the long chain fatty acid elongase Baldspot (ELOVL6) in modifying the ER stress response and disease. We demonstrate that loss of Baldspot rescues degeneration and reduces IRE1 and PERK signaling and cell death in a Drosophila model of retinitis pigmentosa and ER stress (Rh1G69D). Dietary supplementation of stearate bypasses the need for Baldspot activity. Finally, we demonstrate that Baldspot regulates the ER stress response across different tissues and induction methods. Our findings suggest that ELOVL6 is a promising target in the treatment of not only retinitis pigmentosa, but a number of different ER stress-related disorders.

AUTHOR SUMMARY

Differences in genetic background drives disease variability, even among individuals with identical, causative mutations. Identifying and understanding how genetic variation impacts disease expression could improve diagnosis and treatment of patients. Previous work has linked the endoplasmic reticulum (ER) stress response pathway to disease variability. When misfolded proteins accumulate in the ER, the ER stress response returns the cell to its normal state. Chronic ER stress leads to massive amounts of cell death and tissue degeneration. Limiting tissue loss by regulating the ER stress response has been a major focus of therapeutic development. In this study, we characterize a novel regulator of the ER stress response, the long chain fatty acid elongase Baldspot/ELOVL6. In the absence of this enzyme, cells undergoing ER stress display reduced cell death, and degeneration in a Drosophila disease model. Feeding of excess fatty acids increases degeneration to original disease levels, linking the regulatory activity of Baldspot to its enzymatic activity. Finally, we demonstrate that Baldspot can alter the ER stress response under a variety of other ER stress conditions. Our studies demonstrate that Baldspot/ELOVL6 is a ubiquitous regulator of the ER stress response and is a good candidate therapeutic target.
Inducible expression of immediate early genes is regulated through dynamic chromatin association by NF45/ILF2and NF90/ILF3
Authors: Wu Ting-Hsuan , Shi Lingfang , Lowe Anson W. , Nicolls Mark R. , Kao Peter N.
Published: February 2018

Immediate early gene (IEG) transcription is rapidly activated by diverse stimuli without requiring new protein synthesis. This transcriptional regulation is assumed to involve constitutively expressed nuclear factors that are targets of signaling cascades initiated at the cell membrane. NF45 and its heterodimeric partner NF90 are chromatin-interacting proteins that are constitutively expressed and localized predominantly in the nucleus. Previously, NF90 chromatin immunoprecipitation followed by deep sequencing (ChIP-seq) in K562 erythroleukemia cells revealed its enriched association with chromatin at active promoters and strong enhancers. NF90 specifically occupied the promoters of IEGs. Here, ChIP in serum-starved HEK293 cells demonstrated that NF45 and NF90 pre-exist and specifically occupy the promoters of IEG transcription factorsEGR1,FOSandJUN. Cellular stimulation with phorbol myristyl acetate increased NF90 occupancy, while decreasing NF45 occupancy at promoters ofEGR1,FOSandJUN. In HEK293 cells stably transfected with doxycycline-inducible shRNA vectors targeting NF90 or NF45, doxycycline-mediated knockdown of NF90 or NF45 attenuated the inducible expression ofEGR1,FOS, andJUNat the levels of mRNA and protein. NF90 and NF45 operate as constitutively-expressed transcriptional regulators of IEGs. Dynamic chromatin association of NF45 and NF90 at IEG promoters are observed upon stimulation, and NF45 and NF90 contribute to inducible expression of IEGs. NF45 and NF90 operate as chromatin regulators of the immediate early response.
Perceptual insensitivity to higher-order statistical moments of coherent random dot motion
Authors: Waskom Michael L. , Asfour Janeen , Kiani Roozbeh
Published: February 2018

When the visual system analyses distributed patterns of sensory inputs, what features of those distributions does it use? It has been previously demonstrated that higher-order statistical moments of luminance distributions influence perception of static surfaces and textures. Here, we tested whether the brain also represents higher-order moments of dynamic stimuli. We constructed random dot kinematograms where dots moved according to probability distributions that selectively differed in terms of their mean, variance, skewness, or kurtosis. When viewing these stimuli, human observers were sensitive to the mean direction of coherent motion and to the variance of the individual dot displacement angles, but they were insensitive to skewness and kurtosis. Observer behavior accorded with a model of directional motion energy, suggesting that information about higher-order moments is discarded early in the visual processing hierarchy. These results demonstrate that use of higher-order moments is not a general property of visual perception.
A novel surfactant protein is associated with extrapulmonary respiration in lungless salamanders
Authors: Lewis Zachary R. , Dorantes Jorge A. , Hanken James
Published: February 2018

Numerous physiological and morphological adaptations were achieved during the transition to lungless respiration following evolutionary lung loss in plethodontid salamanders, including those that enable efficient gas exchange across extrapulmonary tissue. However, the molecular basis of these adaptations is unknown. Here we show that lungless salamanders express in the skin and buccal cavity—the principal sites of respiratory gas exchange in these species—a novel paralog of the gene Surfactant-Associated Protein C (SFTPC), which is a critical component of pulmonary surfactant expressed exclusively in the lung in other vertebrates. The paralogous gene appears to be found only in salamanders, but, similar to SFTPC, in lunged salamanders it is expressed only in the lung. This heterotopic gene expression, combined with predictions from structural modeling and respiratory tissue ultrastructure, suggest that lungless salamanders produce pulmonary surfactant-like secretions outside the lungs and that the novel paralog of SFTPC might facilitate extrapulmonary respiration in the absence of lungs. Heterotopic expression of the SFTPC paralog may have contributed to the remarkable evolutionary radiation of lungless salamanders, which account for more than two thirds of urodele species alive today.
An annual cycle of gene regulation in the red-legged salamander mental gland: from hypertrophy to expression of rapidly evolving pheromones
Authors: Wilburn Damien B. , Feldhoff Richard C.
Published: February 2018

Cell differentiation is mediated by synchronized waves of coordinated expression for hundreds to thousands of genes, and must be an exquisitely regulated process to produce complex tissues and phenotypes. For many animal species, sexual selection has driven the development of elaborate male ornaments, requiring sex-specific differentiation pathways. One such male ornament is the pheromone-producing mental gland of the red-legged salamander (Plethodon shermani). Mental gland development follows an annual cycle of extreme hypertrophy, production of pheromones for the ~2 month mating season, and then complete resorption before repeating the process in the following year. At the peak of the mating season, the transcriptional and translational machinery of the mental gland are almost exclusively redirected to synthesis of many rapidly evolving pheromones. Of these pheromones, Plethodontid Modulating Factor (PMF) has experienced an unusual history of disjunctive evolution: following gene duplication, positive sexual selection has diversified the protein coding region while the untranslated regions have been conserved by purifying selection. However, the molecular underpinnings that bridge the processes of gland hypertrophy, pheromone synthesis, and disjunctive evolution remain to be determined and are the focus of the present investigation. Using Illumina sequencing, we prepared a de novo transcriptome of the mental gland at six stages of development. Differential expression analysis and immunohistochemistry revealed that the mental gland initially adopts a highly proliferative, almost tumor-like phenotype, followed by a rapid increase in pheromone mRNA and protein levels. One likely player in this transition is Cold Inducible RNA Binding Protein (CIRBP), which selectively and cooperatively binds the highly conserved PMF 3′ UTR. CIRBP, along with other stress response proteins, have seemingly been co-opted to aid in mental gland development by helping to regulate pheromone synthesis. The P. shermani mental gland utilizes a complex system of transcriptional and post-transcriptional gene regulation to facilitate its hypertrophication and pheromone synthesis. The data support the evolutionary interplay of both coding and noncoding segments in rapid gene evolution, and necessitate study of the co-evolution of pheromone gene products along with their transcriptional and translational regulators. Additionally, the mental gland could be a powerful emerging model of regulated proliferation and subsequent resorption of a tissue, within the dermis, thus having potential links to skin cancer biology.
A database of simulated tumor genomes towards accurate detection of somatic small variants in cancer
Authors: Meng Jing , Chen Yi-Ping Phoebe
Published: February 2018

Background

Somatic mutations promote the transformation of normal cells to cancer. Accurate identification of such mutations facilitates cancer diagnosis and treatment. A number of callers have been developed to predict them from paired tumor/normal or unpaired tumor sequencing data. However, the small size of currently available experimentally validated somatic sites limits evaluation and then improvement of callers. Fortunately, NIST reference material NA12878 genome has been well-characterized with publicly available high-confidence genotype calls.

Results

We used BAMSurgeon to create simulated tumors by introducing somatic small variants (SNVs and small indels) into homozygous reference or wildtype sites of NA12878. We generated 135 simulated tumors from 5 pre-tumors/normals. These simulated tumors vary in sequencing and subsequent mapping error profiles, read length, the number of sub-clones, the VAF, the mutation frequency across the genome and the genomic context. Furthermore, these pure tumor/normal pairs can be mixed at desired ratios within each pair to simulate sample contamination.

Conclusions

This database (a total size of 15 terabytes) will be of great use to benchmark somatic small variant callers and guide their improvement.

Contact information

jing.mengrabbit@gmail.com
Identification and characterization of moonlighting long non-coding RNAs based on RNA and protein interactome
Authors: Cheng Lixin , Leung Kwong-Sak
Published: February 2018

Moonlighting proteins are a class of proteins having multiple distinct functions, which play essential roles in a variety of cellular and enzymatic functioning systems. Although there have long been calls for computational algorithms for the identification of moonlighting proteins, research on approaches to identify moonlighting long non-coding RNAs (lncRNAs) has never been undertaken. Here, we introduce a methodology, MoonFinder, for the identification of moonlighting lncRNAs. MoonFinder is a statistical algorithm identifying moonlighting lncRNAs without a priori knowledge through the integration of protein interactome, RNA-protein interactions, and functional annotation of proteins. We identify 155 moonlighting lncRNA candidates and uncover that they are a distinct class of lncRNAs characterized by specific sequence and cellular localization features. The non-coding genes that transcript moonlighting lncRNAs tend to have shorter but more exons and the moonlighting lncRNAs have a localization tendency of residing in the cytoplasmic compartment in comparison with the nuclear compartment. Moreover, moonlighting lncRNAs and moonlighting proteins are rather mutually exclusive in terms of both their direct interactions and interacting partners. Our results also shed light on how the moonlighting candidates and their interacting proteins implicated in the formation and development of cancers and other diseases.
A Single Mechanism of Biogenesis, Initiated and Directed by PIWI Proteins, Explains piRNA Production in Most Animals
Authors: Gainetdinov Ildar , Colpan Cansu , Arif Amena , Cecchini Katharine , Zamore Phillip D.
Published: February 2018

In animals, piRNAs guide PIWI-proteins to silence transposons and regulate gene expression. The mechanisms for making piRNAs have been proposed to differ among cell types, tissues, and animals. Our data instead suggest a single model that explains piRNA production in most animals. piRNAs initiate piRNA production by guiding PIWI proteins to slice precursor transcripts. Next, PIWI proteins direct the stepwise fragmentation of the sliced precursor transcripts, yielding tail-to-head strings of phased pre-piRNAs. Our analyses detect evidence for this piRNA biogenesis strategy across an evolutionarily broad range of animals including humans. Thus, PIWI proteins initiate and sustain piRNA biogenesis by the same mechanism in species whose last common ancestor predates the branching of most animal lineages. The unified model places PIWI-clade Argonautes at the center of piRNA biology and suggests that the ancestral animal—the Urmetazoan—used PIWI proteins both to generate piRNA guides and to execute piRNA function.
Lineage tracing axial progenitors using Nkx1.2CreERT2mice defines their trunk and tail contributions
Authors: Albors Aida Rodrigo , Halley Pamela A. , Storey Kate G.
Published: February 2018

The vertebrate body forms by continuous generation of new tissue from progenitors at the posterior end of the embryo. In mice, these axial progenitors initially reside in the epiblast, from where they form the trunk; and later relocate to the chordo-neural hinge of the tail bud to form the tail. Among them, a small group of bipotent neuromesodermal progenitors (NMPs) are thought to generate the spinal cord and paraxial mesoderm to the end of axis elongation. The study of these progenitors, however, has proven challengingin vivodue to their small numbers and dynamic nature, and the lack of a unique molecular marker to identify them. Here, we report the generation of the Nkx1.2CreERT2transgenic mouse line in which the endogenousNkx1.2promoter drives tamoxifen-inducible CreERT2recombinase. We show that Nkx1.2CreERT2targets axial progenitors, including NMPs and early neural and mesodermal progenitors. Using a YFP reporter, we demonstrate thatNkx1.2-expressing epiblast cells contribute to all three germ layers, mostly neuroectoderm and mesoderm excluding notochord; and continue contributing neural and paraxial mesoderm tissues from the tail bud. This study identifies theNkx1.2-expressing cell population as the source of most trunk and tail tissues in the mouse; and provides a key tool to genetically label and manipulate this progenitor populationin vivo.
Dual signaling of Wamide myoinhibitory peptides through a peptide-gated channel and a GPCR in Platynereis
Authors: Schmidt Axel , Bauknecht Philipp , Williams Elizabeth A. , Augustinowski Katrin , Gründer Stefan , Jékely Gáspár
Published: February 2018

Neuropeptides commonly signal by metabotropic G-protein coupled receptors (GPCRs). In some mollusks and cnidarians, RFamide neuropeptides mediate fast ionotropic signaling by peptide-gated ion channels that belong to the DEG/ENaC family. Here we describe a neuropeptide system with a dual mode of signaling by both a peptide-gated channel and a GPCR. We identified and characterised a peptide-gated channel in the marine annelid Platynereis dumerilii that is specifically activated by Wamide myoinhibitory peptides derived from the same proneuropeptide. The myoinhibitory peptide-gated ion channel (MGIC) belongs to the DEG/ENaC family and is paralogous to RFamide-gated channels. Platynereis myoinhibitory peptides also activate a previously described GPCR, MAG. We measured the potency of all Wamides on both MGIC and MAG and identified peptides that preferentially activate one or the other receptor. Analysis of a single-cell transcriptome resource indicates that MGIC and MAG signal to distinct target neurons. The identification of a Wamide-gated channel suggests that peptide-gated channels are more diverse and widespread in animals than previously appreciated. The possibility of neuropeptide signaling by both ionotropic and metabotropic receptors to different target cells in the same organism highlights an additional level of complexity in peptidergic signaling networks.
Genome sequencing identifies somatic BRAF duplication c.1794_1796dupTAC;p.Thr599dup in pediatric patient with low-grade ganglioglioma
Authors: Miller Katherine E. , Kelly Benjamin , Fitch James , Ross Nicole , Avenarius Matthew R. , Varga Elizabeth , Koboldt Daniel C. , Boué Daniel R. , Magrini Vincent , Coven Scott L. , Finlay Jonathan L. , Cottrell Catherine E. , White Peter , Gastier-Foster Julie M. , Wilson Richard K. , Leonard Jeffrey , Mardis Elaine R.
Published: February 2018

Gangliogliomas (WHO grade I) are rare tumors affecting the central nervous system and are most frequently observed in children. Next-generation sequencing of tumors is being utilized at an increasing rate in both research and clinical settings to characterize the genetic factors that drive tumorigenesis. Here, we report a rare BRAF somatic mutation (NM_004333.4:c.1794_1796dupTAC; p.Thr599dup) in the tumor genome from a pediatric patient in her late teens, who was initially diagnosed with low-grade ganglioglioma at age 13. This duplication of 3 nt introduces a second threonine residue at amino acid 599 of the BRAF protein. Based on previous studies, this variant is likely to increase kinase activity, similar to the well-characterized BRAF p.Val600Glu (V600E) pathogenic variant. In addition, although the p.T599dup somatic mutation has been documented rarely in human cancers, the variant has not been previously reported in ganglioglioma. The identification of this variant presents an opportunity to consider targeted therapy (e.g., BRAF inhibitor) for this patient.
Emissions and production penalties/bonuses associated with non-standard earthmoving loading policies
Authors: Carmichael David G. , Mustaffa Nur Kamaliah
Published: February 2018

Purpose

The performance of earthmoving operations, in terms of emissions, production and cost, is dependent on many variables and has been the study of a number of publications. Such publications look at typical operation design and management, without establishing what the penalties or bonuses might be for non-standard, but still observed, practices. To fill this gap in knowledge, this paper examines alternative loading policies of zero waiting-time loading, fractional loading and double-sided loading, and compares the performance of these with standard single-sided loading.

Design/methodology/approach

Original recursive relationships, that are amenable to Monte Carlo simulation, are derived. Case study data are used to illustrate the emissions, production and cost penalties or bonuses.

Findings

Double-sided loading contributes the least impact to the environment and is the most cost effective. Zero waiting-time loading performs the worst in terms of environmental impact and cost. Minimizing truck waiting times through using fractional loading is generally not an attractive policy because it leads to an increase in unit emissions and unit costs. The consequences of adopting fractional loading are detailed. Optimum unit emissions and optimum unit cost are coincident with respect to fleet size for single- and double-sided loading policies. That is, by minimizing unit cost, as in traditional practice, then least impact on the environment is obtained. Not minimizing unit cost will lead to unnecessary emissions.

Practical implications

The results of this paper will be of interest to those designing and managing earthmoving operations.

Originality/value

All modeling and results presented in the paper do not exist elsewhere in the literature.
Co-producing and re-connecting: a pilot study of recovery community engagement
Authors: Edwards Michael , Soutar Josie , Best David
Published: February 2018

Purpose

The purpose of this paper is to discuss the design and methodology of the REC-CONNECT project and to determine whether a co-produced approach to research in this area between those with lived experience, those delivering recovery support, and those investigating recovery evidence, generated greater project impact.

Design/methodology/approach

A co-productive approach was taken during project planning, training delivery, data collection and community connecting activity. Workshop evaluations were collected at each training session that provided data on worker/peer volunteer wellbeing, workshop efficacy and organisational factors. Community connectors used REC-CAP for evaluating improvements in clients’ community engagement.

Findings

Whilst co-production as a research approach broke down barriers between theory and practice and delivered a wider community asset map, a number of hurdles emerged: buy-in of all participants; culture/competing agendas; overcoming sense of disenfranchisement of people in recovery; and resources, tools and timescales of research requirements.

Research limitations/implications

This is a small study in Sheffield. As such, data are limited. However, the implications spread to other vulnerable groups in other areas are evidenced, and the principles offer sustainability and partnership that go beyond time-limited projects.

Social implications

Co-production as an approach to research in the substance misuse field has a meaningful impact on the “end-user” of people in recovery through empowerment, better connected recovery pathways and evidence-to-practice-based support models.

Originality/value

The project advanced the emerging principle of reciprocal asset-based community development and designed a co-produced model to create a team of professional, volunteer and peer community connectors to engage and connect new individuals to recovery with existing community assets, and who themselves emerged as a community asset through the project.
Dynamic marketing capabilities view on creating market change
Authors: Kachouie Reza , Mavondo Felix , Sands Sean
Published: February 2018

Purpose

The purpose of this paper is to examine the indirect relationship between dynamic capabilities (DCs) and organizational outcomes through matching and creating market change. In addition, the research aims to gain a deeper understanding of the role of marketing in DCs and to extend beyond a simplistic discussion of DCs by studying proactive market orientation and value innovation as specific DCs.

Design/methodology/approach

A questionnaire was developed and data were collected from 270 senior executives. After ensuring reliability and validity, the hypotheses were examined by applying structural equation modeling and Monte Carlo simulation.

Findings

The findings indicate that dynamic marketing capabilities (DMCs) are critical in the reconfiguration of operational marketing capabilities, which in turn lead to enhanced organizational performance. The results also suggest that organizations with enhanced DMCs are able to initiate market disruption and achieve superior performance by out-competing their rivals.

Practical implications

The research provides guidelines for managers wanting to exploit their DMCs by showing that organizations can match the environment, create market turbulence or combine both strategies to fully exploit their DMCs. This study also provides managers with actionable tools that are specific, robust and easily applied.

Originality/value

This study is one of the few to incorporate induced market turbulence into the DC literature and conceptualize, develop and validate scales to measure it. The study provides empirical evidence for the claim that operational marketing capabilities are necessary to utilize the benefits of DMCs.
Market reaction to the transitory effects of IFRS: an examination of disaggregated measures
Authors: Hilliard Theresa , Neidermeyer Presha
Published: February 2018

Purpose

This study examines how International Financial Reporting Standards (IFRS) are applied, disaggregates the cumulative effect of the IFRS transition into magnitude measurements of the standard-to-standard differences (by standard) and management discretionary choices (by choice) and tests which transitory effects at every level of disaggregation alter investor behavior.

Design/methodology/approach

Using hand-collected data from the IFRS 1 disclosures, the research design consists of eight regression models which test fluctuations in investment behavior as a function of varying measures of IFRS adjustments at aggregated and disaggregated levels including magnitude measurements of pronouncements and management choices.

Findings

Findings from the study identify specific standards and management discretionary choices associated with market reaction. Evidence from this study demonstrates the value of disaggregated measures to obtain a more comprehensive understanding of market reaction and associations with transitory effects of IFRS. Findings from the study suggest that the market favors management discretionary choices that decrease retained earnings and potentially increase future net income. Overall, model results suggest that a more comprehensive understanding of the specific standards is obtained that alters market behavior and how the market responds to positive and negative equity adjustments.

Originality/value

This study contributes to the literature examining the capital market effects of IFRS by decomposing the generally accepted accounting principle (GAAP) transition into magnitude measurements of specific standard-to-standard differences (by standard) and management discretionary choices (by choice) to understand how the market responds to the transitory effects of a GAAP change. This is important because it puts regulators, standard setters, investors and researchers on notice that the way in which the authors analyze and measure equity components could be consequential to the authors ability to assess a GAAP change. This study informs all jurisdictions which have adopted or are deliberating the adoption of IFRS how IFRS is being implemented and which areas of application are relevant to investors. Further, market reactions to accounting information pertaining to a GAAP change may only be revealed at the disaggregated and decomposed levels of the retrospective application of the GAAP implementation.
Intellectual capital and firm performance
Authors: Hamdan Allam
Published: February 2018

Purpose

This study sheds light on the relation between intellectual capital and firm performance. The study argues that traditional performance measurement based on accounting is still able to explore the relation between intellectual capital and performance.

Design/methodology/approach

The study was conducted at 198 firms from two Gulf Cooperation Council countries: Kingdom of Saudi Arabia and Kingdom of Bahrain for the period 2014–2016. To measure intellectual capital, the value added intellectual coefficient model was adopted along with two measures of performance: accounting-based performance which is return on assets and market-based performance which is Tobin’s Q, in addition to the Random-Effects Regression.

Findings

Study findings came up with evidences that support the relationship between intellectual capital and accounting-based performance, but negates any relation between intellectual capital and market-based performance. The findings also revealed different results, between Saudi Arabia’s and those of Bahrain.

Originality/value

The study contributes to the debate on the validity of relating intellectual capital to the traditional accounting-based performance.