bluuebunny/crossref_metadata_2025 huggingface dataset:
Luciferase Immunoprecipitation Systems immunoassay is a sensitive, rapid method to detect allergen component-specific IgE
Authors: Lin Adora A. , Perez Natalia S. , Frischmeyer-Guerrerio Pamela A. , Nutman Thomas B.
Published: January 2020

Current assays to detect allergen-specific IgE have constraints related to obtaining pure, conformationally active allergen, variability in allergen extracts, sample volume required, and turnaround time. The luciferase immunoprecipitation systems (LIPS) immunoassay is a fast, sensitive assay created using recombinant antigens that requires a low specimen volume. These assays can also be easily modified to detect multiple antigens and antibody isotypes. Here, we demonstrate the use of LIPS assays as an innovative method to quantitatively measure allergen component-specific IgE in small sample volumes. Sera from healthy volunteers, helminth-infected adults, and peanut-allergic children were screened for IgE to cat using ImmunoCAP. These samples were also measured for IgE against Fel d 1 using LIPS. LIPS signal correlated to cat IgE levels withrS= 0.6204, p < 0.001. The LIPS signal: noise ratio differed significantly between cat IgE-samples and cat IgE+ samples with values > 0.5 kU/L, with the ability to differentiate cat IgE – individuals from cat IgE+ individuals with 85% sensitivity and 76% specificity. Given their rapidity, efficiency, sensitivity, and quantitation over a broad dynamic range, LIPS immunoassays can be a robust and flexible tool with potential uses in allergy research, diagnostics, and treatment.
Coupling between tolerance and resistance for two related Eimeria parasite species
Authors: Balard Alice , Jarquín-Díaz Víctor Hugo , Jost Jenny , Mittné Vivian , Böhning Francisca , Ďureje Ľudovít , Piálek Jaroslav , Heitlinger Emanuel
Published: January 2020

Resistance (host capacity to reduce parasite burden) and tolerance (host capacity to reduce impact on its health for a given parasite burden) manifest two different lines of defence. Tolerance can be independent from resistance, traded-off against it, or the two can be positively correlated because of redundancy in underlying (immune) processes. We here tested whether this coupling between tolerance and resistance could differ upon infection with closely related parasite species. We tested this in experimental infections with two parasite species of the genus Eimeria. We measured proxies for resistance (the (inverse of) number of parasite transmission stages (oocysts) per gram of feces at the day of maximal shedding) and tolerance (the slope of maximum relative weight loss compared to day of infection on number of oocysts per gram of feces at the day of maximal shedding for each host strain) in four inbred mouse strains and four groups of F1 hybrids belonging to two mouse subspecies, Mus musculus domesticus and M. m. musculus. We found a negative correlation between resistance and tolerance against E. falciformis, while the two are uncoupled against E. ferrisi. We conclude that resistance and tolerance against the first parasite species might be traded off, but evolve more independently in different mouse genotypes against the latter. We argue that evolution of the host immune defences can be studied largely irrespective of parasite isolates if resistance-tolerance coupling is absent or weak (E. ferrisi) but host-parasite coevolution is more likely observable and best studied in a system with negatively correlated tolerance and resistance (E. falciformis).
Splice-specific deficiency of the PTSD-associated gene PAC1 leads to a paradoxical age-dependent stress behavior
Authors: Biran Jakob , Gliksberg Michael , Shirat Ido , Swaminathan Amrutha , Levitas-Djerbi Talia , Appelbaum Lior , Levkowitz Gil
Published: January 2020

The pituitary adenylate cyclase-activating polypeptide receptor (PAC1, also known as ADCYAP1R1) is associated with post-traumatic stress disorder and modulation of stress response in general. Alternative splicing of PAC1 results in multiple gene products, which differ in their mode of signalling and tissue distribution. However, the roles of distinct splice variants in the regulation of stress behavior is poorly understood. Alternative splicing of a short exon, which is known as the “hop cassette”, occurs during brain development and in response to stressful challenges. To examine the function of this variant, we generated a splice-specific zebrafish mutant lacking the hop cassette, which we designated ‘hopless’. We show thathoplessmutant larvae display increased anxiety-like behavior, including reduced dark exploration and impaired habituation to dark exposure. Conversely, adulthoplessmutants displayed superior ability to rebound from an acute stressor, as they exhibited reduced anxiety- like responses to an ensuing novelty stress. We propose that the developmental loss of a specific PAC1 splice variant mimics prolonged mild stress exposure, which in the long term, predisposes the organism’s stress response towards a resilient phenotype. Our study presents a unique genetic model demonstrating how early-life state of anxiety paradoxically correlates with reduced stress susceptibility in adulthood.
Adaptive divergence generates distinct plastic responses in two closely relatedSeneciospecies
Authors: Walter Greg M. , Clark James , Cristaudo Antonia , Terranova Delia , Nevado Bruno , Catara Stefania , Paunov Momchil , Velikova Violeta , Filatov Dmitry , Cozzolino Salvatore , Hiscock Simon J. , Bridle Jon R.
Published: January 2020

The evolution of plastic responses to external cues allows species to track the environmental variation they regularly experience. However, it remains unclear how plasticity evolves during adaptation. To test whether distinct patterns of plasticity is associated with recent adaptive divergence, we quantified plasticity for two closely related but ecologically divergent Sicilian daisy species (Senecio, Asteraceae). We sampled c.40 genotypes of each species from natural populations on and around Mt Etna and then reciprocally transplanted multiple clones of each genotype into four field sites along an elevational gradient representing each species’ native range, the edge of their range, and conditions outside their native range. At each elevation we quantified survival and measured leaf traits that included investment (specific leaf area), morphology, chlorophyll fluorescence, pigment content and gene expression. As evidence of adaptive divergence, both species performed better at their native site and better than the species from the other habitat. Traits and differentially expressed genes that changed with elevation in one species often showed little change in the other species, or changed in the opposite direction. Adaptive divergence is therefore associated with the evolution of distinct plastic responses to environmental variation, despite these two species sharing a recent common ancestor.
Exploring the impact of lesser-known social dynamics on wolf populations through an individual-based approach
Authors: Bauduin Sarah , Grente Oksana , Santostasi Nina Luisa , Ciucci Paolo , Duchamp Christophe , Gimenez Olivier
Published: January 2020

The occurrence of wolf populations in human-dominated landscapes is challenging worldwide because of conflicts with human activities. Modeling is an important tool to predict wolf dynamics and expansion, and help in decision making concerning management and conservation. However, some individual behaviors and pack dynamics of the wolf life cycle are still unclear to ecologists. Here we present an individual-based model (IBM) to project wolf populations while exploring the lesser-known processes of the wolf life cycle. IBMs are bottom-up models that simulate the fate of individuals interacting with each other, with population-level properties emerging from the individual-level simulations. IBMs are particularly adapted to represent social species such as the wolf that exhibits complex individual interactions. Our IBM predicts wolf demography including fine-scale individual behavior and pack dynamics based on up-to-date scientific literature. We explore four processes of the wolf life cycle whose consequences on population dynamics are still poorly understood: the pack dissolution following the loss of a breeder, the adoption of young dispersers by packs, the establishment of new packs through budding, and the different types of breeder replacement. While running different versions of the IBM to explore these processes, we also illustrate the modularity and flexibility of our model, an asset to model wolf populations experiencing different ecological and demographic conditions. The different parameterization of pack dissolution, territory establishment by budding, and breeder replacement processes influence the most the projections of wolf populations. As such, these processes require further field investigation to be better understood. The adoption process has a lesser impact on model predictions. Being coded in R to facilitate its understanding, we expect that our model will be used and further adapted by ecologists for their own specific applications.
Novel function acquired by theCulex quinquefasciatusmosquito D7 salivary protein enhances blood feeding on mammals
Authors: Martin-Martin Ines , Paige Andrew , Valenzuela Leon Paola Carolina , Gittis Apostolos G. , Kern Olivia , Bonilla Brian , Chagas Andrezza Campos , Ganesan Sundar , Garboczi David N. , Calvo Eric
Published: January 2020

Adult female mosquitoes require a vertebrate blood meal to develop eggs and continue their life cycle. During blood feeding, mosquito saliva is injected at the bite site to facilitate blood meal acquisition through anti-hemostatic compounds that counteract blood clotting, platelet aggregation, vasoconstriction and host immune responses. D7 proteins are among the most abundant components of the salivary glands of several blood feeding insects. They are members of a family of proteins that have evolved through gene duplication events to encode D7 proteins of several lengths. Here, we examine the ligand binding specificity and physiological relevance of two D7 long proteins, CxD7L1 and CxD7L2, fromCulex quinquefasciatusmosquitoes, the vector of medical and veterinary diseases such as filariasis, avian malaria, and West Nile virus infections. CxD7L1 and CxD7L2 were assayed by microcalorimetry for binding of potential host ligands involved in hemostasis, including bioactive lipids, biogenic amines, and nucleotides/nucleosides. CxD7L2 binds serotonin, histamine, and epinephrine with high affinity as well as the thromboxane A2 analog U-46619 and several cysteinyl leukotrienes, as previously described for other D7 proteins. CxD7L1 does not bind any of the ligands that are bound by CxD7L2. Unexpectedly, CxD7L1 exhibited high affinity for adenine nucleotides and nucleosides, a binding capacity not reported in any D7 family member. We solved the crystal structure of CxD7L1 in complex with bound ADP to 1.97 Å resolution. The binding pocket for ADP is located between the two domains of CxD7L1, whereas all known D7s bind ligands either within the N-terminal or the C-terminal domains. We demonstrated that these two CxD7 long proteins inhibit human platelet aggregation inex vivoexperiments. CxD7L1 and CxD7L2 help blood feeding in mosquitoes by scavenging host molecules that promote vasoconstriction, platelet aggregation, itch, and pain at the bite site. The novel ADP-binding function acquired by CxD7L1 evolved to enhance blood feeding in mammals where ADP plays a key role in platelet aggregation.
Characterizing expression of candidate genes of a glutamate receptor pathway inArabidopsis thalianausing real-time RT-PCR
Authors: Wurdeman Julie , Brooks Tessa Durham
Published: January 2020

TheArabidopsis thalianagenome contains twenty genes that are analogous to mammalian ionotropic glutamate receptors. There are sixteen mammalian glutamate receptors, which are best known for their roles in neuroplasticity, learning, and memory. The large number of glutamate receptors inA. thalianasuggests they play important roles in the plant’s growth and development, possibly serving to regulate function like they do in non-excitable mammalian tissues. A specific glutamate receptor,GLR3.3, is highly expressed in root tissue of plants, and has been found to promote stronger, more coordinated curvature development during the process of gravitropism. Gravitropism is the ability of a plant to change its orientation to that of the gravity vector when displaced from its gravitational set point angle (GSPA). A previous association study identified six candidate genes which were correlated with the same phenotypic characteristics of gravitropism asGLR3.3. Utilizing real time RT-PCR (qRT-PCR) expression profiles were created for each candidate gene, includingGLR3.3.A qRT-PCR method was developed to provide a more quantitative and sensitive way for measuring gene expression than traditional PCR methods. Furthermore, MIQE (Minimum Information for Publication of Quantitative Real-Time PCR Experiments) guidelines were followed to ensure data robustness. Expression profiles that were similar toGLR3.3were hypothesized to be good candidates as cell signaling components of this novel pathway. This is the beginning of a process that will identify aGLR-dependent pathway, the role of this novel pathway in the gravitropic response, and the influence ofGLRsin plant physiology.
Patterns of selection against centrosome amplification in human cell lines
Authors: Dias Louro Marco António , Bettencourt-Dias Mónica , Bank Claudia
Published: January 2020

The presence of extra centrioles, or centrosome amplification, is a hallmark of cancer cells. Centriole numbers in cancer cell populations appear to be at an equilibrium maintained by centriole overproduction and selection, reminiscent of mutation-selection balance. It is not known if the interaction between centriole overproduction and selection can quantitatively explain the intra- and inter-population heterogeneity in centriole numbers.

Here, we define mutation-selection-like models and employ a model selection approach to infer patterns of centriole overproduction and selection in a diverse panel of cell lines. Surprisingly, we infer strong and uniform selection against any number of extra centrioles, in most cell lines. However, we do not detect significant differences in parameter estimates between different cell lines. Finally we assess the accuracy and precision of our inference method and find that it increases non-linearly as a function of the number of sampled cells. We discuss the biological implications of our results and how our methodology can inform future experiments.
The Wg and Dpp morphogens regulate gene expression by modulating the frequency of transcriptional bursts
Authors: Bakker Rachael , Mani Madhav , Carthew Richard W.
Published: January 2020

Morphogen signaling contributes to the proper spatiotemporal expression of genes during development. One method of regulation of signaling-responsive genes is at the level of transcription. Single-cell quantitative studies of transcription have revealed that transcription occurs intermittently, in bursts. Although the effects of many gene regulatory mechanisms on transcriptional bursting have been studied, it remains unclear how morphogen gradients affect this dynamic property of downstream genes. Here we have adapted smFISH for use in theDrosophilawing imaginal disc in order to measure nascent and mature mRNA of genes downstream of the Wg and Dpp morphogen gradients. We compared our experimental results with predictions from stochastic models of transcription. Our results indicate that the transcription levels of these genes appear to share a common method of control via burst frequency modulation. Our data helps further elucidate the link between developmental gene regulatory mechanisms and transcriptional bursting.
Evidence for a growing population of eastern migratory monarch butterflies is currently insufficient
Authors: Thogmartin Wayne E. , Szymanski Jennifer A. , Weiser Emily L.
Published: January 2020

The eastern migratory population of monarch butterflies has experienced a multi-decadal decline, but a recent increase in abundance (to 6.05 ha in winter 2018) has led some observers to question whether the population has reversed its long-standing decline and embarked on a trajectory of increasing abundance. We examined this possibility through changepoint analyses, first assessing whether a change in trajectory existed and whether that change was sufficient to alter our estimated risk for the population. We found evidence of a change in trajectory in 2014, but insufficient statistical support for a significantly increasing population since that time (β = 0.285, 95% CI = −0.127, 0.697). If the population estimate for winter 2019 is ≥4.0 ha, we will then be able to credibly assert the population has been increasing since 2014. However, given estimated levels of time series variability, presumed habitat capacity and no recent change in status or trend, there was a 13.5% probability of observing a population estimate as large or larger than was reported for winter 2018. Despite insufficient evidence for an increasing population, near-term risk of quasi-extinction by 2023 has declined (mean risk declining from 43% to 20%) because of higher abundance estimates since 2014. Our analyses highlight the incredible difficulty in drawing robust conclusions from annual changes in abundance over a short time series, especially for an insect that commonly exhibits considerable year-to-year variation. Thus, we urge caution when drawing conclusions regarding species status and trends for any species for which limited data are available.
BAcTrace a new tool for retrograde tracing of neuronal circuits
Authors: Cachero Sebastian , Gkantia Marina , Bates Alexander S. , Frechter Shahar , Blackie Laura , McCarthy Amy , Sutcliffe Ben , Strano Alessio , Aso Yoshinori , Jefferis Gregory S.X.E.
Published: January 2020

New tools and techniques have enabled many key advances in our understanding of the brain. To elucidate circuit function, it is necessary to identify, record from and manipulate networks of connected neurons. Here we present BAcTrace (BotulinumActivatedTracer), the first fully genetically encoded, retrograde, transsynaptic labelling system. BAcTrace is based onC. botulinumneurotoxin A, Botox, which we have engineered to act as a Trojan horse that jumps retrogradely between neurons to activate an otherwise silent transcription factor. We validate BAcTrace at three connections in theDrosophilaolfactory system and show that it enables electrophysiological recordings of connected neurons. Finally, in a challenging circuit with highly divergent connections, we used Electron Microscopy connectomics to show that BAcTrace correctly identifies 12 out of 16 connections.
Drag-induced directionality switching of kinesin-5 Cin8 revealed by cluster-motility analysis
Authors: Pandey Himanshu , Reithmann Emanuel , Goldstein-Levitin Alina , Al-Bassam Jawdat , Frey Erwin , Gheber Larisa
Published: January 2020

Directed active motion of motor proteins is a vital process in virtually all eukaryotic cells. Nearly a decade ago, the discovery of directionality switching of mitotic kinesin-5 motors challenged the long-standing paradigm that individual kinesin motors are characterized by an intrinsic directionality. While several kinesin motors have now been shown to exhibit context-dependent directionality that can be altered under diverse experimental conditions, the underlying mechanism remains unknown. Here, we studied clustering-induced directionality switching of the mitotic kinesin-5 Cin8, using a fluorescence-based single-molecule motility assay combined with biophysical theory. Based on the detailed characterization of the motility of single motors and clusters of Cin8, we developed a predictive molecular model, that quantitatively agrees with experimental data. This combined approach allowed us to quantify the response of Cin8 motors to external forces as well as the interactions between Cin8 motors, and thereby develop a detailed understanding of the molecular mechanism underlying directionality switching. The main insight is that directionality switching is caused by a single feature of Cin8: an asymmetric response of active motion to forces that oppose motion, here referred to as drag. This general mechanism explains why bidirectional motor proteins are capable of reversing direction in response to seemingly unrelated experimental factors including clustering, changes in the ionic strength of the buffer, increased motor density and molecular crowding, and in motility assays.

Significance Statement

Kinesin-5 motor proteins perform essential functions in chromosome segregation during mitotic cell division. Surprisingly, several kinesin-5 motors have the ability to reverse directionality under different experimental conditions, which contradicts the long-standing paradigm that individual kinesin motors are characterized by an intrinsic directionality. The mechanism underlying this ability to switch directionality has remained elusive. Here, we combine fluorescence-based motility assays and theoretical modeling to analyze cluster-size-dependent motility of the bidirectional kinesin-5 Cin8. Our results show that bidirectional motors can switch directionality because they exhibit an asymmetric response of active motion to drag. This mechanism explains multiple seemingly unrelated experimental factors that have been shown to cause directionality switching of kinesin motors.
New candidates for regulated gene integrity revealed through precise mapping of integrative genetic elements
Authors: Mageeney Catherine M. , Lau Britney Y. , Wagner Julian M. , Hudson Corey M. , Schoeniger Joseph S. , Krishnakumar Raga , Williams Kelly P.
Published: January 2020

Integrative genetic elements (IGEs) are mobile multigene DNA units that integrate into and excise from host bacterial chromosomes. Each IGE usually targets a specific site within a conserved host gene, integrating in a manner that preserves target gene function. However, a small number of bacterial genes are known to be inactivated upon IGE integration and reactivated upon excision, regulating phenotypes of virulence, mutation rate, and terminal differentiation in multicellular bacteria. The list ofregulatedgene integrity (RGI) cases has been slow-growing because IGEs have been challenging to precisely and comprehensively locate in genomes. We present software (TIGER) that maps IGEs with unprecedented precision and withoutattBsite bias. TIGER uses a comparative genomic, ping-pong BLAST approach, based on the principle that the IGE integration module (i.e., itsint-attPregion) is cohesive. The resultant IGEs, along with integrase phylogenetic analysis and gene inactivation tests, revealed 19 new cases of genes whose integrity is regulated by IGEs (includingdut, eccCa1, gntT, hrpB, merA, ompN, prkA, tqsA, traG, yifB, yfaTandynfE), as well as recovering previously known cases (insigK, spsM, comK, mlrA, andhlbgenes). It also recovered known clades of site-promiscuous integrases and identified possible new ones.
Early life stress reduces voluntary exercise and its prevention of diet-induced obesity and metabolic dysfunction in mice
Authors: Eller-Smith Olivia C. , Morris E. Matthew , Thyfault John P. , Christianson Julie A.
Published: January 2020

The development of obesity-related metabolic syndrome (MetS) involves a complex interaction of genetic and environmental factors. One environmental factor found to be significantly associated with MetS is early life stress (ELS). We have previously reported on our mouse model of ELS, induced by neonatal maternal separation (NMS), that displays altered regulation of the hypothalamic-pituitary-adrenal (HPA) axis and increased sensitivity in the urogenital organs, which was attenuated by voluntary wheel running. Here, we are using our NMS model to determine if ELS-induced changes in the HPA axis also influence weight gain and MetS. Naïve (non-stressed) and NMS male mice were given free access to a running wheel and a low-fat control diet at 4-weeks of age. At 16-weeks of age, half of the mice were transitioned to a high fat/sucrose (HFS) diet to investigate if NMS influences the effectiveness of voluntary exercise to prevent diet-induced obesity and MetS. Overall, we observed a greater impact of voluntary exercise on prevention of HFS diet-induced outcomes in naïve mice, compared to NMS mice. Although body weight and fat mass were still significantly higher, exercise attenuated fasting insulin levels and mRNA levels of inflammatory markers in epididymal adipose tissue in HFS diet-fed naïve mice. Only moderate changes were observed in exercised NMS mice on a HFS diet, although this could partially be explained by reduced running distance within this group. Interestingly, sedentary NMS mice on a control diet displayed impaired glucose homeostasis and moderately increased pro-inflammatory mRNA levels in epididymal adipose, suggesting that early life stress alone impairs metabolic function and negatively impacts the therapeutic effect of voluntary exercise.
Cross-sectional and longitudinal associations of family income-to-needs ratio with cortical and subcortical brain volume in adolescent boys and girls
Authors: King Lucy S. , Dennis Emily L. , Humphreys Kathryn L. , Thompson Paul M. , Gotlib Ian H.
Published: January 2020

Deviations in neurodevelopment may underlie the association between lower childhood socioeconomic status and difficulties in cognitive and socioemotional domains. Most previous investigations of the association between childhood socioeconomic status and brain morphology have used cross-sectional designs with samples that span wide age ranges, occluding effects specific to adolescence. Sex differences in the association between childhood socioeconomic status and neurodevelopment may emerge or intensify during adolescence. We used tensor-based morphometry, a whole brain approach, to examine sex differences in the cross-sectional association between normative variation in family income-to-needs ratio (INR) and cortical and subcortical gray and white matter volume during early adolescence (ages 9-13 years, N=147), as well as in the longitudinal association between in INR and change in volume from early to later adolescence (ages 11-16 years, N=109). Biological sex interacted with INR to explain variation in volume in several areas cross-sectionally and longitudinally. Effects were primarily in cortical gray matter areas, including regions of the association cortex and sensorimotor processing areas. Effect sizes tended to be larger in boys than in girls. Biological sex may be an important variable to consider in analyses of the effects of family income on structural neurodevelopment during adolescence.

Highlights

Sex-specific associations of SES with neurodevelopment may emerge in adolescence.

We used a whole-brain approach to examine gray and white matter volume.

Sex interacted with SES to explain variation in volume across adolescence.

Sex is an important variable to consider in analyses of SES and brain volume.
Chlorotoxin Redirects Chimeric Antigen Receptor T Cells for Specific and Effective Targeting of Glioblastoma
Authors: Wang Dongrui , Starr Renate , Chang Wen-Chung , Aguilar Brenda , Alizadeh Darya , Wright Sarah L. , Yang Xin , Brito Alfonso , Sarkissian Aniee , Ostberg Julie R. , Shi Yanhong , Gutova Margarita , Aboody Karen , Badie Behnam , Forman Stephen J. , Barish Michael E. , Brown Christine E.
Published: January 2020

While chimeric antigen receptor (CAR) T cells have demonstrated antitumor activity against glioblastoma (GBM), tumor heterogeneity remains a critical challenge. To more effectively target heterogeneous GBMs, we report the development of a novel peptide-based CAR exploiting the GBM-binding potential of chlorotoxin (CLTX). CLTX bound a greater proportion of tumor cells than GBM-associated antigens EGFR, HER2 and IL13Rα2. CAR T cells bearing CLTX as the targeting domain (CLTX-CAR), mediated potentin vitroandin vivoanti-GBM activity, and efficiently targeted tumors lacking expression of other GBM-associated antigens. Importantly, CLTX-CAR T cells exhibited no observable off-target effector activity against normal cells, or when adoptively transferred into mice. Effective targeting by CLTX-CAR T cells required cell surface expression of matrix metalloproteinase-2 (MMP-2). Our results are the first demonstration of a peptide toxin utilized as a CAR targeting domain, expanding the repertoire of tumor-selective CAR T cells with the potential to reduce antigen escape.

One Sentence Summary

Chimeric antigen receptors incorporating chlorotoxin as the tumor targeting domain recognize and kill glioblastoma with high specificity and potency.
AITL: Adversarial Inductive Transfer Learning with input and output space adaptation for pharmacogenomics
Authors: Sharifi-Noghabi Hossein , Peng Shuman , Zolotareva Olga , Collins Colin C. , Ester Martin
Published: January 2020

Motivation

The goal of pharmacogenomics is to predict drug response in patients using their single- or multi-omics data. A major challenge is that clinical data (i.e. patients) with drug response outcome is very limited, creating a need for transfer learning to bridge the gap between large pre-clinical pharmacogenomics datasets (e.g. cancer cell lines), as a source domain, and clinical datasets as a target domain. Two major discrepancies exist between pre-clinical and clinical datasets: 1) in the input space, the gene expression data due to difference in the basic biology, and 2) in the output space, the different measures of the drug response. Therefore, training a computational model on cell lines and testing it on patients violates the i.i.d assumption that train and test data are from the same distribution.

Results

We propose Adversarial Inductive Transfer Learning (AITL), a deep neural network method for addressing discrepancies in input and output space between the pre-clinical and clinical datasets. AITL takes gene expression of patients and cell lines as the input, employs adversarial domain adaptation and multi-task learning to address these discrepancies, and predicts the drug response as the output. To the best of our knowledge, AITL is the first adversarial inductive transfer learning method to address both input and output discrepancies. Experimental results indicate that AITL outperforms state-of-the-art pharmacogenomics and transfer learning baselines and may guide precision oncology more accurately.

Availability of codes and supplementary material

https://github.com/hosseinshn/AITL

Contact

ccollins@prostatecentre.comandester@cs.sfu.ca
Effect of short-term prescription opioids on DNA methylation of the OPRM1 promoter
Authors: Sandoval-Sierra Jose Vladimir , Salgado García Francisco I , Brooks Jeffrey H , Derefinko Karen J , Mozhui Khyobeni
Published: January 2020

Background

Long-term opioid use has been associated with hypermethylation of the opioid receptor mu 1 (OPRM1) promoter. Very little is currently known about the early epigenetic response to therapeutic opioids. Here we examine whether we can detect DNA methylation changes associated with few days use of prescribed opioids. Genome-wide DNA methylation was assayed in a cohort of 33 opioid-naïve participants who underwent standard dental surgery followed by opioid self-administration. Saliva samples were collected before surgery (visit 1), and at two postsurgery visits at 2.7 ± 1.5 days (visit 2), and 39 ± 10 days (visit 3) after the discontinuation of opioid analgesics.

Results

The perioperative methylome underwent significant changes over the three visits that was primarily due to postoperative inflammatory response and cell heterogeneity. To specifically examine the effect of opioids, we started with a candidate gene approach and evaluated 10 CpGs located in the OPRM1 promoter. There was significant cross-sectional variability in opioid use, and for participants who self-administered the prescribed drugs, the total dosage ranged from 5–210 morphine milligram equivalent (MME). Participants were categorized by cumulative dosage into three groups: <25 MME, 25–90 MME, ≥90 MME. Using mixed effects modeling, 4 CpGs had significant positive associations with opioid dose at 2-tailed p-value < 0.05, and overall, 9 of the 10 OPRM1 promoter CpGs showed the predicted higher methylation in the higher dose groups relative to the lowest dose group. After adjustment for age, cellular heterogeneity, and past tobacco use, the promoter mean methylation also had positive associations with cumulative MME (regression coefficient = 0.0002, 1-tailed p-value = 0.02), and duration of opioid use (regression coefficient = 0.003, 1-tailed p-value = 0.001), but this effect was significant only for visit 3. A preliminary epigenome-wide association study identified a significant CpG in the promoter of the RAS-related signaling gene, RASL10A, that may be predictive of opioid dosage.

Conclusion

The present study provides evidence that the hypermethylation of the OPRM1 promoter is in response to opioid use, and that epigenetic differences in OPRM1 and other sites are associated with short-term use of therapeutic opioids.
Edaravone-Loaded Mesoscale Nanoparticles Treat Cisplatin-Induced Acute Kidney Injury
Authors: Williams Ryan M. , Shah Janki , Mercer Elizabeth , Tian Helen S. , Cheung Justin M. , Dorso Madeline , Jaimes Edgar A. , Heller Daniel A.
Published: January 2020

Cisplatin-induced acute kidney injury (CI-AKI) is a significant co-morbidity of chemotherapeutic regimens. While this condition is associated with substantially lower survival and increased economic burden, there is no pharmacological agent to effectively treat CI-AKI. The disease is hallmarked by acute tubular necrosis of the proximal tubular epithelial cells primarily due to increased oxidative stress. In our prior work, we developed a highly-selective kidney-targeted mesoscale nanoparticle (MNP) that accumulates primarily in the renal proximal tubular epithelial cells while exhibiting no toxicity. Here, we found that MNPs exhibit renal-selective targeting in multiple mouse models of tumor growth with virtually no tumor accumulation. We then evaluated the therapeutic efficacy of MNPs loaded with the reactive oxygen species scavenger edaravone in a mouse model of CI-AKI. We found a marked and significant therapeutic effect with this approach as compared to free drug or empty control MNPs, including improved renal function, histology, and diminution of oxidative stress. These results indicated that renal-selective MNP edaravone delivery holds substantial potential in the treatment of acute kidney injury among patients undergoing cisplatin-based chemotherapy.
Arabidopsis LTR retrotransposons and their regulation by epigenetically activated small RNA
Authors: Lee Seung Cho , Ernst Evan , Berube Benjamin , Borges Filipe , Parent Jean-Sebastien , Ledon Paul , Schorn Andrea , Martienssen Robert A.
Published: January 2020

In Arabidopsis, LTR-retrotransposons are activated by mutations in the chromatin remodeler DECREASE in DNA METHYLATION 1 (DDM1), giving rise to 21-22nt epigenetically activated siRNAs (easiRNAs) that depend on RNA DEPENDENT RNA POLYMERASE 6 (RDR6). We purified virus-like-particles (VLPs) from ddm1 and ddm1rdr6 mutants in which genomic RNA is reverse transcribed into complementary DNA. Next generation short-read and long-read sequencing of VLP DNA (VLP DNA-seq) revealed a comprehensive catalog of active LTR-retrotransposons without the need for mapping transposition, and independent of genomic copy number. Linear replication intermediates of a functionally intact copia element EVADE revealed multiple central polypurine tracts (cPPT), a feature shared with HIV where cPPT promote nuclear localization. For one member of the ATCOPIA52 subfamily (SISYPHUS), cPPT intermediates were not observed, but abundant circular DNA indicated transposon “suicide” by auto-integration within the VLP. easiRNA targeted EVADE genomic RNA, polysome association of GYPSY (ATHILA) subgenomic RNA, and transcription via histone H3 lysine-9 dimethylation. VLP DNA-seq provides a comprehensive landscape of LTR-retrotransposons, and their control at transcriptional, post-transcriptional and reverse transcriptional levels.
From SARS-CoV to Wuhan 2019-nCoV Outbreak: Similarity of Early Epidemic and Prediction of Future Trends
Authors: Chen Zeliang , Zhang Wenjun , Lu Yi , Guo Cheng , Guo Zhongmin , Liao Conghui , Zhang Xi , Zhang Yi , Han Xiaohu , Li Qianlin , Lipkin W. Ian , Lu Jiahai
Published: January 2020

This manuscript has been withdrawn as it was submitted without the full consent of all the authors. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.
Restricted sequence variation inStreptococcus pyogenespenicillin binding proteins
Authors: Hayes Andrew , Lacey Jake A. , Morris Jacqueline M. , Davies Mark R. , Tong Steven Y.C.
Published: January 2020

A recent clinical report has linkedStreptococcus pyogenesβ-lactam antibiotic resistance to mutations in the Penicillin Binding Protein PBP2x. To determine whether this is an isolated case or reflects a broader prevalence of mutations that might confer reduced β-lactam susceptibility, we investigated the relative frequency of penicillin binding protein (PBP) sequence variation within a global database of 9,667S. pyogenesisolates. We found that mutations inS. pyogenesPBPs (PBP2x, PBP1a, PBP1b and PBP2a) occur infrequently across this global database with less than 3 amino acid changes differing between >99% of the global population. Only 4 of the 9,667 strains contained mutations near transpeptidase active sites. The reported PBP2x T553K substitution was not identified. These findings are in contrast to those of 2,520S. pneumococcussequences where PBP mutations are relatively frequent and are often located in key β-lactam binding pockets. These data, combined with the general lack of penicillin resistance reported inS. pyogenesworldwide, suggests that extensive, unknown, constraints restrictS. pyogenesPBP sequence plasticity. These findings imply that while heavy antibiotic pressure may select for mutations in the PBPs, there is currently no evidence of such mutations becoming fixed in theS. pyogenespopulation nor that mutations are being sequentially acquired in the PBPs.

Importance

Penicillin is the first line therapeutic option forStreptococcus pyogenesinfections. Despite the global high prevalence ofS. pyogenesinfections and widespread use of penicillin, reports of resistance to penicillin have been incredibly rare. Recently, penicillin resistance was detected in two clinicalS. pyogenesisolates with accompanying mutations in the active site of the penicillin binding protein PBP2x, raising concerns that penicillin resistance may become more widespread. We screened a global database ofS. pyogenesgenome sequences to investigate the frequency of penicillin binding protein (PBP) mutations, identifying that PBP mutations are uncommon relative toStreptococcus pneumoniae. These findings support clinical observations that penicillin resistance is rare inS. pyogenes, and suggest that there are considerable constraints onS. pyogenesPBP sequence variation.
Time varying connectivity across the brain changes as a function of nicotine abstinence state
Authors: Fedota John R. , Ross Thomas J. , Castillo Juan , McKenna Michael R. , Matous Allison L. , Salmeron Betty Jo , Menon Vinod , Stein Elliot A.
Published: January 2020

Background

The Nicotine Withdrawal Syndrome (NWS) includes affective and cognitive disruptions whose incidence and severity vary across time during acute abstinence. However, most network-level neuroimaging employs static measures of resting state functional connectivity (rsFC), assuming time-invariance, and unable to capture dynamic brain-behavior relationships. Recent advances in rsFC signal processing allow characterization of “time varying connectivity” (TVC), which characterizes network communication between sub-networks that reconfigure over the course of data collection. As such, TVC may more fully describe network dysfunction related to the NWS.

Methods

To isolate alterations in the frequency and diversity of communication across network boundaries as a function of acute nicotine abstinence we scanned cigarette smokers in the nicotine sated and abstinent states and applied a previously-validated method to characterize TVC at a network and nodal level within the brain.

Results

During abstinence, we found brain wide decreases in the frequency of interactions between network nodes in different modular communities (i.e. temporal flexibility; TF). In addition, within a subset of the networks examined the variability of these interactions across community boundaries (i.e. spatiotemporal diversity; STD) also decreased. Finally, within two of these networks the decrease in STD was significantly related to NWS clinical symptoms.

Conclusions

Employing multiple measures of TVC in a within subjects’ design, we characterized a novel set of changes in network communication and link these changes to specific behavioral symptoms of the NWS. These reductions in TVC provide a meso-scale network description of the relative inflexibility of specific large-scale brain networks as a result of acute abstinence.
Liquid-liquid phase separation of full-length prion protein initiates conformational conversionin vitro
Authors: Tange Hiroya , Ishibashi Daisuke , Nakagaki Takehiro , Taguchi Yuzuru , Kamatari Yuji O. , Ozawa Hiroki , Nishida Noriyuki
Published: January 2020

Prion diseases are characterized by accumulation of amyloid fibrils. The causative agent is an infectious amyloid that is comprised solely of misfolded prion protein (PrPSc). Prions can convert PrPCto proteinase-resistant PrP (PrP-res)in vitro; however, the intermediate steps involved in the spontaneous conversion remain unknown. We investigated whether recombinant prion protein (rPrP) can directly convert into PrP-resvialiquid-liquid phase separation in the absence of PrPSc. We found that rPrP underwent liquid-liquid phase separation at the interface of the aqueous two-phase system (ATPS) of polyethylene glycol (PEG) and dextran, whereas single-phase conditions were not inducible. Fluorescence recovery assay after photobleaching revealed that the liquid-solid phase transition occurred within a short time. The aged rPrP-gel acquired proteinase-resistant amyloid accompanied by β-sheet conversion, as confirmed by western blotting, Fourier transform infrared spectroscopy, and Congo red staining. The reactions required both the N-terminal region of rPrP (amino acids 23-89) and kosmotropic salts, suggesting that the kosmotropic anions may interact with the N-terminal region of rPrP to promote liquid-liquid phase separation. Thus, structural conversionvialiquid–liquid phase separation and liquid–solid phase transition are intermediate steps in the conversion of prions.
Profiling the microbial community structure and functional diversity of a dam-regulated river undergoing gravel bar restoration
Authors: Serrana Joeselle M. , Li Bin , Sumi Tetsuya , Takemon Yasuhiro , Watanabe Kozo
Published: January 2020

Background

River restoration efforts are expected to influence and change the diversity and functions of microbial communities following the recovery of habitat characteristics in the river ecosystem. The recreation or restoration of gravel bars in the Trinity River in California aims to rehabilitate the environmental heterogeneity downstream of the dam impounded channel. Here, we profiled the community composition, estimated diversity, and annotated putative metabolic functions of the sediment microbial communities to assess whether the construction and restoration of gravel bars in the Trinity River in California enhanced environmental heterogeneity, with the increase in the microbial beta diversity of these in-channel structures against the free-flowing reach of the main channel with comparison to its undisturbed tributaries.

Results

Microbial community composition of the free-flowing (i.e., no gravel bars) communities were relatively closer regardless of dam influence, whereas the Trinity River gravel bar and tributaries’ gravel bar communities were highly dissimilar. Proteobacteria, Bacteroidetes, and Acidobacteria were the highly abundant sediment microbial phyla on most sites, specifically in the Trinity River gravel bar communities. Putative functional annotation of microbial taxa revealed that chemoheterotrophy and aerobic chemoheterotrophy were the most prevalent microbial processes, with the Trinity River gravel bars having relatively higher representations. The considerably large abundance of heterotrophic taxa implies that gravel bars provide suitable areas for heterotrophic microorganisms with metabolic functions contributing to the net respiration in the river.

Conclusions

Our results provide supporting evidence on the positive impact of habitat restoration being conducted in the Trinity River with the non-dam influenced, undisturbed tributaries as the basis of comparison. Gravel bar recreation and restoration contributed to the increased microbial biodiversity through the restoration of environmental heterogeneity at the river scale. We provided valuable insights into the potential microbial processes in the sediment that might be contributing to the biogeochemical processes carried out by the microbial communities in the Trinity River. The significant positive correlation between the functional diversity of the identified microbial taxa and beta diversity suggests that differences in the detected metabolic functions were closely related to dissimilarities in community composition.
Divergent thermal challenges elicit convergent stress signatures in aposymbioticAstrangia poculata
Authors: Wuitchik DM , Almanzar A , Benson BE , Brennan SA , Chavez JD , Liesegang MB , Reavis JL , Reyes CL , Schniedewind MK , Trumble IF , Davies SW
Published: January 2020

Anthropogenic climate change threatens corals globally and both high and low temperatures are known to induce coral bleaching. However, coral stress responses across wide thermal breadths are rarely explored. In addition, it is difficult to disentangle the role of symbiosis on the stress response of obligately symbiotic coral hosts. Here, we leverage aposymbiotic colonies of the facultatively symbiotic coral,Astrangia poculata, which lives naturally with and without its algal symbiont, to examine how broad thermal challenges influence coral hosts.A. poculatawere collected from their northern range limit and thermally challenged in two independent 16-day common garden experiments (heat and cold challenge) and behavioral responses to food stimuli and genome-wide gene expression profiling (TagSeq) were performed. Both thermal challenges elicited significant reductions in polyp extension. However, five times as many genes were differentially expressed under cold challenge compared to heat challenge. Despite more genes responding to cold challenge, there was significant overlap in which genes were differentially expressed across thermal challenges. These convergently responding genes (CRGs) were associated with downregulation of motor functions and nematocysts while others were consistent with stress responses previously identified in tropical corals. The fact that these responses were observed in aposymbiotic colonies highlights that many genes previously implicated in stress responses in symbiotic species may simply represent the coral’s stress response in or out of symbiosis.