bluuebunny/crossref_metadata_2025 huggingface dataset:
FaceLift: a transparent deep learning framework to beautify urban scenes
Authors: Joglekar Sagar , Quercia Daniele , Redi Miriam , Aiello Luca Maria , Kauer Tobias , Sastry Nishanth
Published: January 2020

In the area of computer vision, deep learning techniques have recently been used to predict whether urban scenes are likely to be considered beautiful: it turns out that these techniques are able to make accurate predictions. Yet they fall short when it comes to generating actionable insights for urban design. To support urban interventions, one needs to go beyondpredictingbeauty, and tackle the challenge ofrecreatingbeauty. Unfortunately, deep learning techniques have not been designed with that challenge in mind. Given their ‘black-box nature’, these models cannot be directly used to explain why a particular urban scene is deemed to be beautiful. To partly fix that, we propose a deep learning framework (which we name FaceLift1) that is able to bothbeautifyexisting urban scenes (Google Street Views) andexplainwhich urban elements make those transformed scenes beautiful. To quantitatively evaluate our framework, we cannot resort to any existing metric (as the research problem at hand has never been tackled before) and need to formulate new ones. These new metrics should ideally capture the presence (or absence) of elements that make urban spaces great. Upon a review of the urban planning literature, we identifyfivemain metrics: walkability, green spaces, openness, landmarks and visual complexity. We find that, across all the five metrics, the beautified scenes meet the expectations set by the literature on what great spaces tend to be made of. This result is further confirmed by a 20-participant expert survey in which FaceLift has been found to be effective in promoting citizen participation. All this suggests that, in the future, as our framework’s components are further researched and become better and more sophisticated, it is not hard to imagine technologies that will be able to accurately and efficiently support architects and planners in the design of the spaces we intuitively love.
Analysing and optimizing the electrolysis efficiency of a lithium cell based on the electrochemical and multiphase model
Authors: Zhao Qian-Wen , Liu Cheng-Lin , Sun Ze , Yu Jian-Guo
Published: January 2020

Based on an electrochemical multiphysical simulation, a method for analysing electrolysis efficiency has been presented that considers the energy consumption required to produce a single kilogram of lithium and for the production of lithium, rather than the voltage in various parts. By adopting them as the criteria for analysing electrolysis efficiency in the lithium cell, several structural parameters have been optimized, such as the anode radius and anode–cathode distance. These parameters strongly affect the cell voltage and the velocity field distribution, which has a significant impact on the concentration distribution. By integrating the concentration distribution, the lithium production and energy consumption per kilogram, lithium is computed. By appointing the minimum of the chlorine and lithium concentration as the secondary reaction intensity, it is clear where the secondary reaction intensity is strong in the cell. The structure of a lithium electrolysis cell has been optimized by applying an orthogonal design approach, with the energy consumption notably decreasing from 35.0 to 28.3 kWh (kg Li)
−1
and the lithium production successfully increasing by 0.17 mol.
A multivariate analysis of women's mating strategies and sexual selection on men's facial morphology
Authors: Clarkson Tessa R. , Sidari Morgan J. , Sains Rosanna , Alexander Meredith , Harrison Melissa , Mefodeva Valeriya , Pearson Samuel , Lee Anthony J. , Dixson Barnaby J. W.
Published: January 2020

The strength and direction of sexual selection via female choice on masculine facial traits in men is a paradox in human mate choice research. While masculinity may communicate benefits to women and offspring directly (i.e. resources) or indirectly (i.e. health), masculine men may be costly as long-term partners owing to lower paternal investment. Mating strategy theory suggests women's preferences for masculine traits are strongest when the costs associated with masculinity are reduced. This study takes a multivariate approach to testing whether women's mate preferences are context-dependent. Women (
n
= 919) rated attractiveness when considering long-term and short-term relationships for male faces varying in beardedness (clean-shaven and full beards) and facial masculinity (30% and 60% feminized, unmanipulated, 30% and 60% masculinized). Participants then completed scales measuring pathogen, sexual and moral disgust, disgust towards ectoparasites, reproductive ambition, self-perceived mate value and the facial hair in partners and fathers. In contrast to past research, we found no associations between pathogen disgust, self-perceived mate value or reproductive ambition and facial masculinity preferences. However, we found a significant positive association between moral disgust and preferences for masculine faces and bearded faces. Preferences for beards were lower among women with higher ectoparasite disgust, providing evidence for ectoparasite avoidance hypothesis. However, women reporting higher pathogen disgust gave higher attractiveness ratings for bearded faces than women reporting lower pathogen disgust, providing support for parasite-stress theories of sexual selection and mate choice. Preferences for beards were also highest among single and married women with the strongest reproductive ambition. Overall, our results reflect mixed associations between individual differences in mating strategies and women's mate preferences for masculine facial traits.
Characterizing the limits of human stability during motion: perturbative experiment validates a model-based approach for the Sit-to-Stand task
Authors: Holmes Patrick D. , Danforth Shannon M. , Fu Xiao-Yu , Moore Talia Y. , Vasudevan Ram
Published: January 2020

Falls affect a growing number of the population each year. Clinical methods to assess fall risk usually evaluate the performance of specific motions such as balancing or Sit-to-Stand. Unfortunately, these techniques have been shown to have poor predictive power, and are unable to identify the portions of motion that are most unstable. To this end, it may be useful to identify the set of body configurations that can accomplish a task under a specified control strategy. The resulting strategy-specific boundary between stable and unstable motion could be used to identify individuals at risk of falling. The recently proposed Stability Basin is defined as the set of configurations through time that do not lead to failure for an individual under their chosen control strategy. This paper presents a novel method to compute the Stability Basin and the first experimental validation of the Stability Basin with a perturbative Sit-to-Stand experiment involving forwards or backwards pulls from a motor-driven cable with 11 subjects. The individually-constructed Stability Basins are used to identify when a trial fails, i.e. when an individual must switch from their chosen control strategy (indicated by a step or sit) to recover from a perturbation. The constructed Stability Basins correctly predict the outcome of trials where failure was observed with over90%accuracy, and correctly predict the outcome of successful trials with over95%accuracy. The Stability Basin was compared to three other methods and was found to estimate the stable region with over45%more accuracy in all cases. This study demonstrates that Stability Basins offer a novel model-based approach for quantifying stability during motion, which could be used in physical therapy for individuals at risk of falling.
Automated analysis of scanning electron microscopic images for assessment of hair surface damage
Authors: Chu Fanny , Anex Deon S. , Jones A. Daniel , Hart Bradley R.
Published: January 2020

Mechanical damage of hair can serve as an indicator of health status and its assessment relies on the measurement of morphological features via microscopic analysis, yet few studies have categorized the extent of damage sustained, and instead have depended on qualitative profiling based on the presence or absence of specific features. We describe the development and application of a novel quantitative measure for scoring hair surface damage in scanning electron microscopic (SEM) images without predefined features, and automation of image analysis for characterization of morphological hair damage after exposure to an explosive blast. Application of an automated normalization procedure for SEM images revealed features indicative of contact with materials in an explosive device and characteristic of heat damage, though many were similar to features from physical and chemical weathering. Assessment of hair damage with tailing factor, a measure of asymmetry in pixel brightness histograms and proxy for surface roughness, yielded 81% classification accuracy to an existing damage classification system, indicating good agreement between the two metrics. Further ability of the tailing factor to score features of hair damage reflecting explosion conditions demonstrates the broad applicability of the metric to assess damage to hairs containing a diverse set of morphological features.
Preparation and characterization of waterborne alkyd-amino baking coatings based on waste polyethylene terephthalate
Authors: Yun Xia , Xin-yi Yang , Dun-hong Gong , Yong-bo Ding , Liang Shen
Published: January 2020

The recycling of polyethylene terephthalate (PET) is the most attractive method for PET waste management because it not only decreases the load on landfill space, but also provides opportunities for reducing the use of raw petrochemical products. Therefore, in this investigation, neopentyl glycol is used for alcoholysis of waste PET, and glycolyzed PET product was applied for preparation of the waterborne alkyd resin. Furthermore, the waterborne alkyd-amino baking coatings were prepared from the waterborne alkyd based on glycolyzed waste PET and melamine formaldehyde resin and applied on tinplate. The waterborne alkyd-amino resin films showed excellent adhesion, balanced hardness and flexibility, high gloss and outstanding chemical resistance except for alkali resistance owing to hydrolysis of ester bonds.
An experimental approach to evaluate the potential of drones in terrestrial mammal research: a gregarious ungulate as a study model
Authors: Schroeder Natalia M. , Panebianco Antonella , Gonzalez Musso Romina , Carmanchahi Pablo
Published: January 2020

Research on the use of unmanned aircraft systems (UAS) in wildlife has made remarkable progress recently. Few studies to date have experimentally evaluated the effect of UAS on animals and have usually focused primarily on aquatic fauna. In terrestrial open arid ecosystems, with relatively good visibility to detect animals but little environmental noise, there should be a trade-off between flying the UAS at high height above ground level (AGL) to limit the disturbance of animals and flying low enough to maintain count precision. In addition, body size or social aggregation of species can also affect the ability to detect animals from the air and their response to the UAS approach. To address this gap, we used a gregarious ungulate, the guanaco (
Lama guanicoe
), as a study model. Based on three types of experimental flights, we demonstrated that (i) the likelihood of miscounting guanacos in images increases with UAS height, but only for offspring and (ii) higher height AGL and lower UAS speed reduce disturbance, except for large groups, which always reacted. Our results call into question mostly indirect and observational previous evidence that terrestrial mammals are more tolerant to UAS than other species and highlight the need for experimental and species-specific studies before using UAS methods.
On the correspondence of deviances and maximum-likelihood and interval estimates from log-linear to logistic regression modelling
Authors: Jing W. , Papathomas M.
Published: January 2020

Consider a set of categorical variables

P

where at least one, denoted by
Y
, is binary. The log-linear model that describes the contingency table counts implies a logistic regression model, with outcome
Y
. Extending results from Christensen (1997,
Log-linear models and logistic regression
, 2nd edn. New York, NY, Springer), we prove that the maximum-likelihood estimates (MLE) of the logistic regression parameters equals the MLE for the corresponding log-linear model parameters, also considering the case where contingency table factors are not present in the corresponding logistic regression and some of the contingency table cells are collapsed together. We prove that, asymptotically, standard errors are also equal. These results demonstrate the extent to which inferences from the log-linear framework translate to inferences within the logistic regression framework, on the magnitude of main effects and interactions. Finally, we prove that the deviance of the log-linear model is equal to the deviance of the corresponding logistic regression, provided that no cell observations are collapsed together when one or more factors in

P

∖
{
Y
}

become obsolete. We illustrate the derived results with the analysis of a real dataset.
Individual-based model of juvenile eel movement parametrized with computational fluid dynamics-derived flow fields informs improved fish pass design
Authors: Padgett Thomas E. , Thomas Robert E. , Borman Duncan J. , Mould David C.
Published: January 2020

European eel populations have declined markedly in recent decades, caused in part by in-stream barriers, such as weirs and pumping stations, which disrupt the upstream migration of juvenile eels, or elvers, into rivers. Eel passes, narrow sloping channels lined with substrata that enable elvers to ascend, are one way to mitigate against these barriers. Currently, studded eel tiles are a popular substrate. This study is the first to evaluate the flow fields within studded eel tiles and to model the swimming performance of elvers using cellular automata (CA) and individual- (or agent-) based models. Velocities and flow depths predicted by a computational fluid dynamics model of studded eel tiles are first validated against published values for a single installation angle–discharge combination. The validated model is then used to compute three-dimensional flow fields for eel passes at five different installation angles and three inflow discharges. CA and individual-based models are employed to assess upstream passage efficiency for a range of elver sizes. The individual-based model approximates measured passage efficiencies better than the CA model. Passage efficiency is greatest for shallow slopes, low discharges and large elvers. Results are synthesized into an easy-to-understand graphic to help practitioners improve eel pass designs.
Enhanced visible-light photocatalytic activity of anatase-rutile mixed-phase nano-size powder given by high-temperature heat treatment
Authors: Ishigaki Takamasa , Nakada Yusuke , Tarutani Naoki , Uchikoshi Tetsuo , Tsujimoto Yoshihiro , Isobe Masaaki , Ogata Hironori , Zhang Chenning , Hao Dong
Published: January 2020

Nano-size EVONIK AEROXIDE
®
P25 titanium dioxide, TiO
2
, powder was heat-treated at temperatures, 700–900°C, in air. An X-ray diffraction study showed that the P25 powder is composed of approximately 20 and approximately 80 mass% of rutile and anatase phases, respectively. It was also shown that the transformation from anatase to rutile induced by high-temperature heat treatment was almost completed at 750°C, whereas a small amount (less than 3 mass%) of anatase phase was still left even in the powder heat-treated at 900°C. The transformation behaviour was consistent with results obtained by Raman scattering spectroscopy. Raman experiments also indicated that high-temperature heating induced the formation of oxide ion vacancies. Powders were dispersed in methyl orange (MO) aqueous solution, and the bleach rate of MO was measured to evaluate photocatalytic activity under ultraviolet (UV)- and visible-light irradiation. After the heat treatment, the UV-light photocatalytic performance sharply deteriorated. Interestingly, visible-light photocatalytic activity was enhanced by high-temperature heating and reached the highest performance for an 800°C-heated sample, indicating that the P25 powder obtained high visible-light photocatalytic performance after heat treatment. Even after 900°C heat treatment, the photocatalytic performance was higher than that of as-received powder. Enhancement of photocatalytic activities was discussed in relation to visible light absorption and charge carrier transfer.
Migratory lineages rapidly evolve larger body sizes than non-migratory relatives in ray-finned fishes
Authors: Burns Michael D. , Bloom Devin D.
Published: January 2020

Migratory animals respond to environmental heterogeneity by predictably moving long distances in their lifetime. Migration has evolved repeatedly in animals, and many adaptations are found across the tree of life that increase migration efficiency. Life-history theory predicts that migratory species should evolve a larger body size than non-migratory species, and some empirical studies have shown this pattern. A recent study analysed the evolution of body size between diadromous and non-diadromous shads, herrings, anchovies and allies, finding that species evolved larger body sizes when adapting to a diadromous lifestyle. It remains unknown whether different fish clades adapt to migration similarly. We used an adaptive landscape framework to explore body size evolution for over 4500 migratory and non-migratory species of ray-finned fishes. By fitting models of macroevolution, we show that migratory species are evolving towards a body size that is larger than non-migratory species. Furthermore, we find that migratory lineages evolve towards their optimal body size more rapidly than non-migratory lineages, indicating body size is a key adaption for migratory fishes. Our results show, for the first time, that the largest vertebrate radiation on the planet exhibited strong evolutionary determinism when adapting to a migratory lifestyle.
Differential processing and localization of human Nocturnin controls metabolism of mRNA and nicotinamide dinucleotide metabolites
Authors: Abshire Elizabeth T. , Hughes Kelsey , Diao Rucheng , Pearce Sarah , Trievel Raymond C. , Rorbach Joanna , Freddolino Peter L. , Goldstrohm Aaron C.
Published: January 2020

Nocturnin (NOCT) is a eukaryotic enzyme that belongs to a superfamily of exoribonucleases, endonucleases, and phosphatases. In this study, we analyze the expression, processing, localization, and cellular functions of human NOCT. We demonstrate that the NOCT protein is differentially expressed and processed in a cell and tissue type specific manner as a means to control its localization to the cytoplasm or mitochondria. Our studies also show that the N-terminus of NOCT is necessary and sufficient to confer mitochondrial localization. We then measured the impact of cytoplasmic NOCT on the transcriptome and report that it regulates the levels of hundreds of mRNAs that are enriched for components of signaling pathways, neurological functions, and regulators of osteoblast differentiation. Recent biochemical data indicate that NOCT dephosphorylates nicotinamide adenine dinucleotide (NAD) metabolites, and thus we measured the effect of NOCT on these cofactors in cells. We find that NOCT increases NAD(H) and decreases NADP(H) levels in a manner dependent on its intracellular localization. Collectively, our data indicate that NOCT can regulate levels of both mRNAs and NADP(H) cofactors in manner specified by its intracellular localization.
Within and cross species predictions of plant specialized metabolism genes using transfer learning
Authors: Moore Bethany M. , Wang Peipei , Fan Pengxiang , Lee Aaron , Leong Bryan , Lou Yann-Ru , Schenck Craig A. , Sugimoto Koichi , Last Robert , Lehti-Shiu Melissa D. , Barry Cornelius S. , Shiu Shin-Han
Published: January 2020

Plant specialized metabolites mediate interactions between plants and the environment and have significant agronomical/pharmaceutical value. Most genes involved in specialized metabolism (SM) are unknown because of the large number of metabolites and the challenge in differentiating SM genes from general metabolism (GM) genes. Plant models likeArabidopsis thalianahave extensive, experimentally derived annotations, whereas many non-model species do not. Here we employed a machine learning strategy, transfer learning, where knowledge fromA. thalianais transferred to predict gene functions in cultivated tomato with fewer experimentally annotated genes. The first tomato SM/GM prediction model using only tomato data performs well (F-measure=0.74, compared with 0.5 for random and 1.0 for perfect predictions), but from manually curating 88 SM/GM genes, we found many mis-predicted entries were likely mis-annotated. When the SM/GM prediction models built withA. thalianadata were used to filter out genes where theA. thaliana-based model predictions disagreed with tomato annotations, the new tomato model trained with filtered data improved significantly (F-measure=0.92). Our study demonstrates that SM/GM genes can be better predicted by leveraging cross-species information. Additionally, our findings provide an example for transfer learning in genomics where knowledge can be transferred from an information-rich species to an information-poor one.
Microbial Source Tracking in the Love Creek Watershed, Delaware (USA)
Authors: Main Christopher R. , Tyler Robin , Lopez Karen , Heurta Serigo
Published: January 2020

Fecal contamination of waterways in Delaware pose an ongoing problem for environmental and public health. For monitoring efforts,Enterococcushas been widely adopted by the state to indicate the presence of fecal matter from warm-blooded animals and to establish Primary and Secondary Contact Recreation criteria. In this study, we examined sites within the Love Creek watershed, a tributary of the Rehoboth bay, using next-generation sequencing and SourceTracker to determine sources of potential fecal contamination and compared to bacterial communities to chemical and nutrient concentrations. Microbial community from fecal samples of 10 different types of animals and 1 human sample were used to generate a fecal library for community-based microbial source tracking. Orthophosphate and total dissolved solids were among the major factors associated with community composition. SourceTracker analysis of the monthly samples from the Love Creek watershed indicated the majority of the microbial community were attributed to “unknown” sources, i.e. wildlife. Those that attribute to known sources were primarily domestic animals, i.e. cat and dog. These results suggest that at the state level these methods are capable of giving the start for source tracking as a means to understanding bacterial contamination.
Antisense targeting of decoy exons can reduce intron retention and increase protein expression in human erythroblasts
Authors: Parra Marilyn , Zhang Weiguo , Vu Jonathan , DeWitt Mark , Conboy John G.
Published: January 2020

The decoy exon model has been proposed to regulate a subset of intron retention (IR) events involving predominantly larger introns (>1kb). Splicing reporter studies have shown that decoy splice sites are essential for activity, suggesting that decoys act by engaging intron-terminal splice sites and competing with cross-intron interactions required for intron excision. The decoy model predicts that antisense oligonucleotides blocking decoy splice sites in endogenous pre-mRNA should increase productive gene expression by reducing IR. Indeed, we now demonstrate that targeting a decoy 5′ splice site in the O-GlcNAc transferase (OGT) gene reduced IR from ∼80% to ∼20% in primary human erythroblasts, accompanied by increases in spliced OGT RNA and OGT protein expression. The remaining OGT IR was refractory to antisense treatment and might be mediated by independent mechanism(s). In contrast, other retained introns were strongly dependent on decoy function, since IR was nearly eliminated by antisense targeting of 5′ splice sites. Genes in the latter group encode the widely expressed splicing factor (SF3B1), and the erythroid-specific structural protein, alpha-spectrin (SPTA1). These results show that modulating decoy exon function can dramatically alter IR, and suggest that dynamic regulation of decoy exons could be a mechanism to fine tune gene expression post-transcriptionally in many cell types.
Multi valent DNA vaccine against group A human rotavirus: anin-silicoinvestigation
Authors: Dutta Kunal
Published: January 2020

Gastroenteritis due to single rotavirus causes huge economic loss annually. Severity of rotaviral diarrhoea among children is primarily manifested by different combinations of G and P types. Rotavirus surveillance studies resulted in two ambitious globally licensed vaccine namely, Rotarix and RotaTaq and a few other. However, post-vaccination surveillance studies indicate, vaccine failure and other complications such as intussusception, environmental enteric dysfunction,etc. Herein, we design a multivalent DNA vaccine against rotavirus and tested its efficiency by usingin silicotools. Two main neutralizing rotaviral antigensi.e, VP7 and VP8 were taken into account and respectively 390, 450 known sequences of different serogroup have been analyzed to obtain a consensus sequence for epitope prediction. Epitopes specific for MHC-I and -II were predicted using IEDB and chosen based on their best IC50value and CPR. A good binding profile with a monoclonal antibody specific for B-cell antigens is displayed by all epitopes they were found to be non-allergenic in the human host. Ethnic specificity of the epitopes is also within acceptable range except for South African and Central American populations. We use pBI-CMV1 bidirectional mammalian expression vector to design the DNA vaccine, where we stapled manually integrated epitopes for VP7 and VP8 at MCS1 and 2 respectively. In conclusion, this study provides a new set of data for a new DNA vaccine against rotavirus.
Structural Analysis of the PATZ1 BTB domain homodimer
Authors: Piepoli Sofia , Alt Aaron Oliver , Atilgan Canan , Mancini Erika J. , Erman Batu
Published: January 2020

PATZ1 is a transcriptional repressor belonging to the ZBTB family that is functionally expressed in T-lymphocytes, as well as in a ubiquitous fashion. PATZ1 targets theCd8gene in lymphocyte development and interacts with the p53 protein to control genes important in proliferation and DNA damage response. PATZ1 exerts its activity through an N-terminal BTB domain that mediates dimerization and co-repressor interactions and a C-terminal zinc finger motif-containing domain that mediates DNA binding. Here, the crystal structures of the murine and zebrafish PATZ1 BTB domains are reported at 2.3 and 1.8 Å resolution respectively. The structures reveal that, like other ZBTB structures, the PATZ1 BTB domain forms a stable homodimer and likely binds co-repressors through a lateral surface groove that is formed upon dimerization. Analysis of the lateral groove reveals a large acidic patch in this region which contrasts previously resolved basic co-repressor binding interfaces in other ZBTB proteins. A large 30 amino acids glycine- and alanine-rich central loop, unique to mammalian PATZ1 amongst all ZBTB proteins, could not be resolved likely due to its flexibility. Modelling of this loop indicates that it can participate in the dimerization interface of BTB monomers.

Synopsis

The crystal structures of the PATZ1 BTB domain in mammals and fish are homodimers. The core dimer conformation of these BTB proteins is dynamically stable, despite the presence of highly flexible regions in the dimerization interface.
A calibrated optogenetic toolbox of stable zebrafish opsin lines
Authors: Antinucci P , Dumitrescu AS , Deleuze C , Morley HJ , Leung K , Hagley T , Kubo F , Baier H , Bianco IH , Wyart C
Published: January 2020

Optogenetic actuators with diverse spectral tuning, ion selectivity and kinetics are constantly being engineered providing powerful tools for controlling neural activity with subcellular resolution and millisecond precision. Achieving reliable and interpretablein vivooptogenetic manipulations requires reproducible actuator expression and calibration of photocurrents in target neurons. Here, we developed nine transgenic zebrafish lines for stable opsin expression and calibrated their efficacyin vivo. We first used high-throughput behavioural assays to compare opsin ability to elicit or silence neural activity. Next, we performedin vivowhole-cell electrophysiological recordings to quantify the amplitude and kinetics of photocurrents and test opsin ability to precisely control spiking. We observed substantial variation in efficacy, associated with differences in both opsin expression level and photocurrent characteristics, and identified conditions for optimal use of the most efficient opsins. Overall, our calibrated optogenetic toolkit will facilitate the design of controlled optogenetic circuit manipulations.
A multi-layered systems approach for renal cell carcinoma
Authors: Cooley Lindsay S. , Rudewicz Justine , Souleyreau Wilfried , Clarke Kim , Falciani Francesco , Dufies Maeva , Verbeke Stephanie , Emanuelli Andrea , Benzekry Sebastien , Taing Cécile , Ribot Emeline Julie , Miraux Sylvain , Lambrechts Diether , Modave Elodie , Pineau Raphael , Derieppe Marie-Alix , Ambrosetti Damien , Bernhard Jean-Christophe , Ravaud Alain , Négrier Sylvie , Ferrero Jean-Marc , Pagès Gilles , Nikolski Macha , Bikfalvi Andreas
Published: January 2020

Renal cell carcinoma (RCC) still lacks prognostic and predictive biomarkers to monitor the disease and the response to therapy. The usual strategy in translational research is to start from human samples, to identify molecular markers and gene networks and then to functionally validate themin vitroand in animal models. We devised herein a completely opposite strategy from “mouse to man” by performing an aggressiveness screen and used functional genomics, imaging, clinical data and computational approaches in order to discover molecular pathways and players in renal cancer development and metastasis. Multiple cell lines for primary tumor growth, survival in the blood circulation and lung metastasis or metastatic spread from the primary tumor were generated and analyzed using a multi-layered approach which includes large-scale transcriptome, genome and methylome analyses. Transcriptome and methylome analyses demonstrated distinct clustering in three different groups. Remarkably, DNA sequencing did not show significant genomic variations in the different groups which indicates absence of clonal selection during thein vivoamplification process. Transcriptome analysis revealed distinct signatures of tumor aggressiveness which were validated in patient cohorts. Methylome analysis of full-length DNA allowed clustering of the same groups and revealed clinically relevant signatures. Furthermore, we identified SAA2 and CFB as soluble prognostic and predictive biomarkers of the therapeutic response. We also uncovered IL34 as another soluble prognostic biomarker and key regulator of renal cell carcinoma (RCC) progression. This was also functionally validatedin vivo,and a mathematical model of IL34-dependent primary tumor growth and metastasis development was provided. These results indicate that such multilayered analysis in a RCC animal model leads to meaningful results that are of translational significance.

One Sentence Summary

An aggressiveness screen with multilayer systems analysis to identify signatures and biomarkers for renal cell carcinoma aggressiveness.
A binary arginine methylation switch on histone H3 Arginine 2 regulates its interaction with WDR5
Authors: Lorton Benjamin M. , Harijan Rajesh K. , Burgos Emmanuel S. , Bonanno Jeffery B. , Almo Steven C. , Shechter David
Published: January 2020

Histone H3 arginine 2 (H3R2) is post-translationally modified in three different states by “writers” of the protein arginine methyltransferase (PRMT) family. H3R2 methylarginine isoforms include PRMT5-catalyzed mono- and symmetric di-methylation (me1, me2s), and PRMT6-catalyzed me1 and asymmetric dimethylation (me2a). WD-40 repeat-containing protein 5 (WDR5) is an epigenetic “reader” protein that interacts with H3R2 and is a subunit of numerous chromatin-modifying complexes, such as theMixedLineageLeukemia (MLL) H3 lysine 4 methyltransferase complex. Previous studies suggested that MLL recruitment to chromatin was specified by the high-affinity interaction between WDR5 and H3R2me2s. However, our prior biological data prompted the hypothesis that WDR5 may also interact with H3R2me1 to recruit MLL activity. Here, using highly accurate quantitative binding analysis combined with high-resolution crystal structures of WDR5 in complex with unmodified (me0) and me1/me2s L-Arginine amino acids and in complex with H3R2me1 peptide, we provide a rigorous biochemical study of this important biological interaction. Despite modest structural differences at the binding interface, our study supports an interaction model regulated by a binary arginine methylation switch: H3R2me2a prevents interaction with WDR5, whereas H3R2me0/me1/me2s are equally permissive.
Trait-environment relationships are predictive, but not general across species
Authors: Frances Dachin N. , Barber Amelia J. , Tucker Caroline M.
Published: January 2020

Understanding the relationships between organisms and their environments is increasingly important given human impacts on global conditions. However, predicting how community diversity and composition will change in the future remains challenging (Mouquetet al2015). One recent approach is to use traits to mechanistically inform how environmental conditions affect performance (i.e., trait-environment relationships), under the assumptions that these measures relate to each other in predictive and general ways. Unfortunately, results have been inconsistent, ignore phenotypic plasticity, and rely heavily on observational data (Shipleyet al2016). We evaluated the predictability and generality of trait-environment relationships in a controlled experimental microcosm system of four daphniid species. We cultured each species along a stressful gradient (conspecific density), measuring performance (fecundity) and traits related to performance (body length, 2nd antenna length, eye diameter, relative growth rate, and age at first reproduction). Using structural equation models, we evaluated the role of traits in mediating changes in individual fecundity in response to conspecific density. We built models for each species separately considering within-species trait variation, and for all species together by considering all trait variation across the four species. Results from this controlled system highlight that the relationship between individual traits and the environment (conspecific density) is strong and predictive of performance (fecundity), both within- and across-species. However, the specific trait-environment relationships which predicted fecundity differed for each species and differed from the relationships observed in the interspecific model, suggesting a lack of generality. These results will inform and improve the use of traits as a tool for predicting how changing environments will impact species abundances and distributions.
Integrative analysis identifies candidate tumor microenvironment and intracellular signaling pathways that define tumor heterogeneity in NF1
Authors: Banerjee Jineta , Allaway Robert J , Taroni Jaclyn N , Baker Aaron , Zhang Xiaochun , Moon Chang In , Pratilas Christine A , Blakeley Jaishri O , Guinney Justin , Hirbe Angela , Greene Casey S , Gosline Sara JC
Published: January 2020

Neurofibromatosis type 1 is a monogenic syndrome that gives rise to numerous symptoms including cognitive impairment, skeletal abnormalities, and growth of benign nerve sheath tumors. Nearly all NF1 patients develop cutaneous neurofibromas (cNFs), which occur on the skin surface, while 40-60% of patients develop plexiform neurofibromas (pNFs) which are deeply embedded in the peripheral nerves. Patients with pNFs have a ∼10% lifetime chance of these tumors becoming malignant peripheral nerve sheath tumors (MPNSTs). These tumors have a severe prognosis and few treatment options other than surgery. Given the lack of therapeutic options available to patients with these tumors, identification of druggable pathways or other key molecular features could aid ongoing therapeutic discovery studies. In this work, we used statistical and machine learning methods to analyze 77 NF1 tumors with genomic data to characterize key signaling pathways that distinguish these tumors and identify candidates for drug development. We identified subsets of latent gene expression variables that may be important in the identification and etiology of cNFs, pNFs, other neurofibromas, and MPNSTs. Furthermore, we characterized the association between these latent variables and genetic variants, immune deconvolution predictions, and protein activity predictions.
ATR Inhibitors as Potent Modulators of DNA End Resection Capacity
Authors: Dibitetto Diego , Sims Jennie R. , Ascenção Carolline F.R. , Feng Kevin , Freire Raimundo , Smolka Marcus B.
Published: January 2020

DNA end resection is a key step in homologous recombination-mediated DNA repair. The ability to manipulate resection capacity is expected to be a powerful strategy to rationally modulate DNA repair outcomes in cancer cells and induce selective cell lethality. However, clinically compatible strategies to manipulate resection are not yet well established. Here we find that long-term inhibition of the ATR kinase has a drastic effect on DNA end resection. Inhibition of ATR over multiple cell division cycles depletes the pool of pro-resection factors and prevents RAD51 as well as RAD52-mediated DNA repair, leading to toxic end-joining and hypersensitivity to PARP inhibitors. The effect is markedly distinct from acute ATR inhibition, which blocks RAD51-mediated repair but not resection and RAD52-mediated repair. Our findings reveal a key pro-resection function for ATR and define how ATR inhibitors can be used for effective manipulation of DNA end resection capacity and DNA repair outcomes in cancer cells.
Backstepping Based Automatically Controlled Angiogenic Inhibition Therapy
Authors: Doruk R. Ozgur
Published: January 2020

In this work, we present an automatically controlled angiogenic inhibition therapy where the variation profile of the inhibitory agent is generated by a control law that is derived using a back-stepping based control methodology. The angiogenic inhibition is described by a second order model representing the dynamics of tumor and supporting vasculature volumes. Backstepping control recursively stabilizes that dynamics and generates automatic control laws that allows the tumor volume to stay at a desired value. The desired value will be kept at one thousandth of its initial value. This will lead to a very small injection at the steady state. This is important as zero injection may lead to regrow of the tumor. The results will be presented in tabular and graphical forms. Tabular results present the variation of maximum injection rate and setup time. Graphical results present the variation of tumor and supporting vasculature volumes, injection rate and the tracking error between the reference and actual tumor volumes. In addition, we will also perform a simulation to test the capability of the closed loop to accomodate the parametric uncertainties in the rate constants. The uncertainties are represented by a random deviation in the range ±10% times the nominal value of the effected parameter. The control laws will be kept the same and the simulations will be repeated by 1000 times and each result will be superimposed on the graph. The area occupied by the curves will show the relative capability of the designs.
ntJoin: Fast and lightweight assembly-guided scaffolding using minimizer graphs
Authors: Coombe Lauren , Nikolić Vladimir , Chu Justin , Birol Inanc , Warren René L.
Published: January 2020

The ability to generate high-quality genome sequences is cornerstone to modern biological research. Even with recent advancements in sequencing technologies, many genome assemblies are still not achieving reference-grade. Here, we introduce ntJoin, a tool that leverages structural synteny between a draft assembly and reference sequence(s) to contiguate and correct the former with respect to the latter. Instead of alignments, ntJoin uses a lightweight mapping approach based on a graph data structure generated from ordered minimizer sketches. The tool can be used in a variety of different applications, including improving a draft assembly with a reference-grade genome, a short read assembly with a draft long read assembly, and a draft assembly with an assembly from a closely-related species. When scaffolding a human short read assembly using the reference human genome or a long read assembly, ntJoin improves the NGA50 length 23- and 13-fold, respectively, in under 13 m, using less than 11 GB of RAM. Compared to existing reference-guided assemblers, ntJoin generates highly contiguous assemblies faster and using less memory.

Availability and implementation

ntJoin is written in C++ and Python, and is freely available athttps://github.com/bcgsc/ntjoin.

Contact

lcoombe@bcgsc.ca
RNA-Binding and Prion Domains: The Yin and Yang of Phase Separation
Authors: Gotor Nieves Lorenzo , Armaos Alexandros , Calloni Giulia , Vabulas R. Martin , de Groot Natalia Sanchez , Tartaglia Gian Gaetano
Published: January 2020

Biomolecular condensates are membrane-less organelles mainly composed of proteins and RNAs that organize intracellular spaces and regulate biochemical reactions. The ability of proteins and RNAs to phase separate is encoded in their sequences, yet it is still unknown which domains drive the process and what are their specific roles. Here, we systematically investigated the human and yeast proteomes to find regions promoting biomolecular condensation. Using advanced computational models to predict the phase separation propensity of proteins, we designed a set of experiments to investigate the contributions of Prion-Like Domains (PrLDs) and RNA-Binding Domains (RBDs). We found that while just one PrLD is sufficient to drive protein condensation, multiple RBDs are needed to modulate the dynamicity of the assemblies. In the case of stress granule protein Pub1 we show that the PrLD promotes sequestration of protein partners and the RBD confers liquid-like behaviour to the condensate. Our work sheds light on the fine interplay between RBDs and PrLD to regulate formation of membrane-less organelles, opening up the avenue for their manipulation.
Drug mechanism-of-action discovery through the integration of pharmacological and CRISPR screens
Authors: Gonçalves Emanuel , Segura-Cabrera Aldo , Pacini Clare , Picco Gabriele , Behan Fiona M. , Jaaks Patricia , Coker Elizabeth A. , van der Meer Donny , Barthorpe Andrew , Lightfoot Howard ,   GDSC Screening Team, Leach Andrew R. , Lynch James T. , Sidders Ben , Crafter Claire , Iorio Francesco , Fawell Stephen , Garnett Mathew J.
Published: January 2020

Low success rates during drug development are due in part to the difficulty of defining drug mechanism-of-action and molecular markers of therapeutic activity. Here, we integrated 199,219 drug sensitivity measurements for 397 unique anti-cancer drugs and genome-wide CRISPR loss-of-function screens in 484 cell lines to systematically investigatein cellulardrug mechanism-of-action. We observed an enrichment for positive associations between drug sensitivity and knockout of their nominal targets, and by leveraging protein-protein networks we identified pathways that mediate drug response. This revealed an unappreciated role of mitochondrial E3 ubiquitin-protein ligaseMARCH5in sensitivity to MCL1 inhibitors. We also estimated drug on-target and off-target activity, informing on specificity, potency and toxicity. Linking drug and gene dependency together with genomic datasets uncovered contexts in which molecular networks when perturbed mediate cancer cell loss-of-fitness, and thereby provide independent and orthogonal evidence of biomarkers for drug development. This study illustrates how integrating cell line drug sensitivity with CRISPR loss-of-function screens can elucidate mechanism-of-action to advance drug development.
A mitochondria-targeted antioxidant and a thyroid hormone affect carotenoid ketolase gene expression and bill redness in zebra finches
Authors: Cantarero Alejandro , Andrade Pedro , Carneiro Miguel , Moreno-Borrallo Adrián , Alonso-Alvarez Carlos
Published: January 2020

Conspicuous ornaments in animals can evolve to reveal individual quality when their production/maintenance costs make them reliable as signals or if their expression level is intrinsically linked to quality by some unfalsifiable mechanism (quality indices). The latter has been mostly associated with traits constrained by body size. However, red ketocarotenoid-based coloured ornaments may also have evolved as quality indices because their production could be closely linked to individual metabolism and, particularly, to the cell respiration at the inner mitochondrial membrane (IMM). This mechanism would supposedly not depend on resource (yellow carotenoids) availability, thus discarding allocation trade-offs. A gene coding for a ketolase enzyme (CYP2J19) responsible for converting dietary yellow carotenoids to red ketocarotenoids has recently been described in birds. It is not known, however, if this ketolase is involved in mitochondrial metabolism and if its expression level and activity is resource independent. Here, we manipulated the metabolism of captive male zebra finches by an antioxidant designed to penetrate the IMM (mitoTEMPO) and a thyroid hormone (triiodothyronine; T3) with known hypermetabolic effects. The expression levels of a ketocarotenoid-based ornament (bill redness) andCYP2J19were measured. MitoTEMPO downregulatedCYP2J19expression, supporting the mitochondrial involvement in ketolase function. T3 also reducedCYP2J19expression, but at an intermediate dosage, this effect being buffered by mitoTEMPO. Bill redness seemed to show a similar interacting effect. Nevertheless, this faded whenCYP2J19expression level was controlled for as a covariate. We argue that the well-known mitoTEMPO effect in reducing mitochondrial reactive oxygen species (ROS) production (particularly superoxide) could have interfered on redox signalling mechanisms controlling ketolase transcription. High T3 levels, contrarily, can lead to high ROS production but also trigger compensatory mechanisms, which may explain the U-shaped effect with dosage onCYP2J19expression levels. BillCYP2J19expression values were also positively correlated to redness and circulating substrate carotenoid levels. Nonetheless, treatment effects did not change when controlling for blood carotenoid concentration, suggesting that resource-availability dependence was irrelevant. Finally, our findings reveal a role for thyroid hormones in the expression of carotenoid-based ornaments that has virtually been ignored until now.