bluuebunny/crossref_metadata_2025 huggingface dataset:
Partial selfing eliminates inbreeding depression while maintaining genetic diversity
Authors: Chelo Ivo M. , Afonso Bruno , Carvalho Sara , Theologidis Ioannis , Goy Christine , Pino-Querido Ania , Proulx Stephen R. , Teotónio Henrique
Published: October 2017

Classical theory on the origin and evolution of selfing and outcrossing relies on the role of inbreeding depression created by unlinked partially-deleterious recessive alleles to predict that individuals from natural populations predominantly self or outcross. Comparative data indicates, however, that maintenance of partial selfing and outcrossing at intermediate frequencies is common in nature. In part to explain the presence of mixed reproductive modes within populations, several hypotheses regarding the evolution of inbreeding depression have been put forward based on the complex interaction of linkage and identity disequilibrium among fitness loci, together with Hill-Robertson effects. We here ask what is the genetic basis of inbreeding depression so that populations with intermediate selfing rates can eliminate it while maintain potentially adaptive genetic diversity. For this, we use experimental evolution in the nematodeC. elegansunder partial selfing and compare it to the experimental evolution of populations evolved under exclusive selfing and predominant outcrossing. We find that the ancestral risk of extinction upon enforced inbreeding by selfing is maintained when populations evolve under predominant outcrossing, but reduced when populations evolve under partial or exclusive selfing. Analysis of genome-wide single-nucleotide polymorphism (SNP) during experimental evolution and after enforced inbreeding suggests that, under partial selfing, populations were purged of unlinked deleterious recessive alleles that segregate in the ancestral population, which in turn allowed the expression of unlinked overdominant fitness loci. Taken together, these observations indicate that populations evolving under partial selfing gain the short-term benefits of selfing, in purging deleterious recessive alleles, but also the long-term benefits of outcrossing, in maintaining genetic diversity that may important for future adaptation.
Evolution of cold acclimation in temperate grasses (Pooideae)
Authors: Schubert Marian , Grønvold Lars , Sandve Simen R. , Hvidsten Torgeir R. , Fjellheim Siri
Published: October 2017

In the past 50 million years climate cooling has triggered the expansion of temperate biomes. During this period, many extant plant lineages in temperate biomes evolved from tropical ancestors and adapted to seasonality and cool conditions. Among the Poaceae (grass family), one of the subfamilies that successfully shifted from tropical to temperate biomes is the Pooideae (temperate grasses). Subfamily Pooideae contains the most important crops cultivated in the temperate regions including wheat (Triticum aestivum) and barley (Hordeum vulgare). Due to the need of well-adapted cultivars, extensive research has produced a large body of knowledge about the mechanisms underlying cold adaptation in cultivated Pooideae species. Especially cold acclimation, a process which increases the frost tolerance during a period of non-freezing cold, plays an important role. Because cold adaptation is largely unexplored in lineages that diverged early in the evolution of the Pooideae, little is known about the evolutionary history of cold acclimation in the Pooideae. Here we test if several species of early diverging lineages exhibit increased frost tolerance after a period of cold acclimation. We further investigate the conservation of five well-studied gene families that are known to be involved in the cold acclimation of Pooideae crop species. Our results indicate that cold acclimation exists in early diverging lineages, but that genes involved in regulation of cold acclimation are not conserved. The investigated gene families show signs of lineage-specific evolution and support the hypothesis that gene family expansion is an important mechanism in adaptive evolution.
Assigning enzyme sequences to orphan and novel reactions using knowledge of substrate reactive sites
Authors: Hadadi Noushin , MohamadiPeyhani Homa , Miskovic Ljubisa , Seijo Marianne , Hatzimanikatis Vassily
Published: October 2017

Thousands of biochemical reactions with characterized activities are orphan, meaning they cannot be assigned to a specific enzyme, leaving gaps in metabolic pathways. Novel reactions predicted by pathway-generation tools also lack associated sequences, limiting protein engineering applications. Associating orphan and novel reactions with known biochemistry and suggesting enzymes to catalyze them is a daunting problem. We propose a new method, BridgIT, to identify candidate genes and protein sequences for these reactions, and this method introduces, for the first time, information about the enzyme binding pocket into reaction similarity comparisons. BridgIT assesses the similarity of two reactions, one orphan and one well-characterized, nonorphan reaction, using their substrate reactive sites, their surrounding structures, and the structures of the generated products to suggest protein sequences and genes that catalyze the most similar non-orphan reactions as candidates for also catalyzing the orphan ones.

We performed two large-scale validation studies to test BridgIT predictions against experimental biochemical evidence. For the 234 orphan reactions from KEGG 2011 (a comprehensive enzymatic reaction database) that became non-orphan in KEGG 2018, BridgIT predicted the exact or a highly related enzyme for 211 of them. Moreover, for 334 out of 379 novel reactions in 2014 that were later catalogued in KEGG 2018, BridgIT predicted the exact or highly similar enzyme sequences.

BridgIT requires knowledge about only three connecting bonds around the atoms of the reactive sites to correctly identify protein sequences for 93% of analyzed enzymatic reactions. Increasing to six connecting bonds allowed for the accurate identification of a sequence for nearly all known enzymatic reactions.

SIGNIFICANCE STATEMENT

Recent advances in synthetic biochemistry have resulted in a wealth of novel hypothetical enzymatic reactions that are not matched to protein-encoding genes, deeming them “orphan”. Nearly half of known metabolic enzymes are also orphan, leaving important gaps in metabolic network maps. Proposing genes for the catalysis of orphan reactions is critical for applications ranging from biotechnology to medicine. In this work, a novel computational method, BridgIT, identified a potential enzyme sequence to orphan reactions and nearly all theoretically possible biochemical transformations, providing candidate genes to catalyze these reactions to the research community. BridgIT online tool will allow researchers to fill the knowledge gaps in metabolic networks and will act as a starting point for designing novel enzymes to catalyze non-natural transformations.
Modeling the growth and decline of pathogen effective population size provides insight into epidemic dynamics and drivers of antimicrobial resistance
Authors: Volz Erik M. , Didelot Xavier
Published: October 2017

Abstract

Non-parametric population genetic modeling provides a simple and flexible approach for studying demographic history and epidemic dynamics using pathogen sequence data. Existing Bayesian approaches are premised on stationary stochastic processes which may provide an unrealistic prior for epidemic histories which feature extended period of exponential growth or decline. We show that non-parametric models defined in terms of the growth rate of the effective population size can provide a more realistic prior for epidemic history. We propose a non-parametric autoregressive model on the growth rate as a prior for effective population size, which corresponds to the dynamics expected under many epidemic situations. We demonstrate the use of this model within a Bayesian phylodynamic inference framework. Our method correctly reconstructs trends of epidemic growth and decline from pathogen genealogies even when genealogical data is sparse and conventional skyline estimators erroneously predict stable population size. We also propose a regression approach for relating growth rates of pathogen effective population size and time-varying variables that may impact the replicative fitness of a pathogen. The model is applied to real data from rabies virus andStaphylococcus aureusepidemics. We find a close correspondence between the estimated growth rates of a lineage of methicillin-resistantS. aureusand population-level prescription rates ofβ-lactam antibiotics. The new models are implemented in an open source R package calledskygrowthwhich is available athttps://mrc-ide.github.io/skygrowth/.
Forest Dormouse (Dryomys nitedula) populations in southern Italy belong to a deeply divergent evolutionary lineage
Authors: Bisconti R. , Aloise G. , Siclari A. , Fava V. , Provenzano M , Arduino P. , Chiocchio A. , Nascetti G. , Canestrelli D.
Published: October 2017

The Forest Dormouse (Dryomys nitedula) is a small rodent with a wide, albeit severely fragmented distribution, ranging from central Europe to central Asia. Within the Italian region,D. nitedulapopulations are restricted to forested mountain areas of two largely disconnected regions, the eastern Alps and the Calabria region, where two distinct subspecies (D. nitedula intermediusandD. nitedula aspromontis, respectively) have been described on the basis of phenotypic characters (i.e., fur colour). Here we analysedD. nitedulasamples from both regions, to investigate patterns of genetic divergence and phylogenetic relationship among these two populations. Genetic variation was studied at the level of one mitochondrial (cytochrome b gene) and three nuclear gene fragments (exon1 of the interstitial retinoid-binding protein, exon 10 of the growth hormone receptor, and recombination activating gene 1). Phylogenetic analyses were performed using Maximum Likelihood and Bayesian inference methods.D. n. aspromontisandD. n. intermediuswere found to be reciprocally monophyletic in all the phylogenetic analyses, and the genetic divergence observed between them at the mitochondrialCYTBgene was conspicuous (HKY: 0.044) when compared to previously observed values among many sister species of rodents. Our results clearly show thatD. nitedula aspromontisis a deeply divergent, narrow endemic evolutionary lineage, and its conservation needs should be carefully evaluated in the near future. Moreover, such deep genetic divergence, together with phenotypic differentiation betweenD. n. intermediusandD. n. aspromontis,suggest thatD. nitedulapopulations in southern Italy might belong to a distinct, previously unrecognized species.
Spatial sorting as the spatial analogue of natural selection
Authors: Phillips Ben L. , Perkins T. Alex
Published: October 2017

In most systems, dispersal occurs despite clear fitness costs to dispersing individuals. Theory posits that spatial heterogeneity in habitat quality pushes dispersal rates to evolve towards zero, while temporal heterogeneity in habitat quality favours non-zero dispersal rates. One aspect of dispersal evolution that has received a great deal of recent attention is a process known as spatial sorting, which has been referred to as a “shy younger sibling” of natural selection. More precisely, spatial sorting is the process whereby variation in dispersal ability is sorted along density clines and will, in nature, often be a transient phenomenon. Despite this transience, spatial sorting is likely a general mechanism behind non-zero dispersal in spatiotemporally varying environments. While generally transient, spatial sorting is persistent on invasion fronts, where its effect cannot be ignored, causing rapid evolution of traits related to dispersal. Spatial sorting is described in several elegant models, yet these models require a high level of mathematical sophistication and are not accessible to most evolutionary biologists or their students. Here, we frame spatial sorting in terms of the classic haploid and diploid models of natural selection. We show that, on an invasion front, spatial sorting can be conceptualized precisely as selection operating through space rather than (as with natural selection) time, and that genotypes can be viewed as having both spatial and temporal aspects of fitness. The resultant model is strikingly similar to classic models of natural selection. This similarity renders the model easy to understand (and to teach), but also suggests that many established theoretical results around natural selection could apply equally to spatial sorting.
Growth hormone transgenesis disrupts immune function in muscle of coho salmon (Oncorhynchus kisutch) impacting cross-talk with growth systems
Authors: Alzaid Abdullah , Kim Jin-Hyoung , Devlin Robert H. , Martin Samuel A.M. , Macqueen Daniel J.
Published: October 2017

The suppression of growth during infection should facilitate resource allocation towards effective immune function. Work supporting this hypothesis has been recently reported in teleosts, demonstrating immune-responsive regulation of the insulin-like growth factor (IGF) system - a key endocrine growth pathway that acts downstream of growth hormone (GH). Skeletal muscle is the main target for growth and energetic storage in fish, yet little is known about how growth is regulated in this tissue during an immune response. We addressed this knowledge gap by characterizing muscle immune responses in size-matched coho salmon (Oncorhynchus kisutch) achieving different growth rates. We compared a wild-type strain with two GH transgenic groups achieving either maximal or highly-suppressed growth – an experimental design that separates GH’s direct effects from its influence on growth rate. Fish were sampled 30h post-injection with PBS (control) or mimics of bacterial (peptidoglycan) or viral (Poly:IC) infection. We quantified the mRNA level expression of genes from the GH, GH receptor (GHR), IGF hormone, IGF1 receptor (IGF-1R) and IGF binding protein (IGFBP) families, along with marker genes for muscle growth and host defence genes involved in inflammatory or antiviral responses. We provide strong evidence for dampened immunity in the GH transgenics compared to wild-type animals. Strikingly, the muscle of GH transgenics achieving rapid growth showed no detectable antiviral response, coupled with evidence of a constitutive inflammatory state. GH and IGF system gene expression was also strongly altered by GH transgenesis and fast growth, both for baseline expression levels and responses to immune stimulation. Overall, our findings demonstrate that GH transgenesis disrupts normal immune function and growth-immune cross-talk in muscle, with implications for the health and welfare of farmed salmon.
The relationship between spatial configuration and functional connectivity of brain regions
Authors: Bijsterbosch Janine D. , Woolrich Mark W. , Glasser Matthew F. , Robinson Emma C. , Beckmann Christian F. , Van Essen David C. , Harrison Samuel J. , Smith Stephen M.
Published: October 2017

Brain connectivity is often considered in terms of the communication between functionally distinct brain regions. Many studies have investigated the extent to which patterns of coupling strength between multiple neural populations relates to behavior. For example, studies have used "functional connectivity fingerprints" to characterise individuals' brain activity. Here, we investigate the extent to which the exact spatial arrangement of cortical regions interacts with measures of brain connectivity. We find that the shape and exact location of brain regions interact strongly with the modelling of brain connectivity, and present evidence that the spatial arrangement of functional regions is strongly predictive of non-imaging measures of behaviour and lifestyle. We believe that, in many cases, cross-subject variations in the spatial configuration of functional brain regions are being interpreted as changes in functional connectivity. Therefore, a better understanding of these effects is important when interpreting the relationship between functional imaging data and cognitive traits.
DNA lesions proximity modulates damage tolerance pathways inEscherichia coli
Authors: Chrabaszcz Élodie , Laureti Luisa , Pagès Vincent
Published: October 2017

The genome of all organisms is constantly threatened by numerous agents that cause DNA damages. When the replication fork encounters an unrepaired DNA lesion, two DNA damage tolerance pathways are possible: error-prone translesion synthesis (TLS) that requires specialized DNA polymerases, and error-free Damage Avoidance (DA) that relies on homologous recombination. The balance between these two mechanisms is essential since it defines the level of mutagenesis during lesion bypass, allowing genetic variability and adaptation to the environment, but also introducing the risk of generating genome instability. Here we report that the mere proximity of replication-blocking lesions that arise inEscherichia coli’s genome during a genotoxic stress, leads to a strong increase in the use of the error-prone TLS. We show that this increase is caused by the local inhibition of homologous recombination due to the overlapping of single-stranded DNA regions generated downstream the lesions. This increase in TLS is independent of SOS activation, but its mutagenic effect is additive with the one of SOS. Hence, the combination of SOS induction and lesions proximity leads to a strong increase in TLS that becomes the main lesion tolerance pathway used by the cell during a genotoxic stress.
The evolution of the temporal program of genome replication
Authors: Agier Nicolas , Delmas Stéphane , Zhang Qing , Fleiss Aubin , Jaszczyszyn Yan , van Dijk Erwin , Thermes Claude , Weigt Martin , Cosentino-Lagomarsino Marco , Fischer Gilles
Published: October 2017

Comparative analyses of temporal programs of genome replication revealed either a nearly complete conservation between closely related species or a comprehensive reprogramming between distantly related species. Therefore, many important questions on the evolutionary remodeling of replication timing programs remain unanswered. To address this issue, we generated genome-wide replication timing profiles for ten yeast species from the genus Lachancea, covering a continuous evolutionary range from closely related to more divergent species. The comparative analysis of these profiles revealed that the replication program linearly evolves with increasing evolutionary divergence between these species. We found that the evolution of the timing program mainly results from a high evolutionary turnover rate of the cohort of active replication origins. We detected about one thousand evolutionary events of losses of active replication origins and gains of newborn origins since the species diverged from their last common ancestor about 80 million years ago. We show that the relocation of active replication origins is independent from synteny breakpoints, suggesting that chromosome rearrangements did not drive the evolution of the replication programs. Rather, origin gains and losses are linked both in space, along chromosomes, and in time, along the same branches of the phylogenetic tree. New origins continuously arise with on average low to medium firing efficiencies and increase in efficiency and earliness as they evolutionarily age. Yet, a subset of newborn origins emerges with high firing efficiency and origin losses occur concomitantly to their emergence and preferentially in their direct chromosomal vicinity. These key findings on the evolutionary birth, death and conservation of active replication origins provide the first description of how the temporal program of genome replication has evolved in eukaryotes.
Effects of Force Fields on the Conformational and Dynamic Properties of Amyloid β(1-40) Dimer Explored by Replica Exchange Molecular Dynamics Simulations
Authors: Watts Charles R. , Gregory Andrew , Frisbie Cole , Lovas Sándor
Published: October 2017

Alzheimer’s disease is histologically marked by fibrils of Amyloid beta (Aβ) peptide within the extracellular matrix. Fibrils themselves are benign compared to the cytotoxicity of the oligomers and pre-fibrillary aggregates. The conformational space and structural ensembles of Aβ peptides and their oligomers in solution are inherently disordered and proven to be challenging to study. Optimum force field selection for molecular dynamics (MD) simulations and the biophysical relevance of results are still unknown. We compared the conformational space of the Aβ(1–40) dimers by 300 ns replica exchange MD simulations at physiological temperature (310 K) using: the AMBER-ff99sb-ILDN, AMBER-ff99sb*-ILDN, AMBER-ff99sb-NMR, and CHARMM22* force fields. Statistical comparisons of simulation results to experimental data and previously published simulations utilizing the CHARMM22* and CHARMM36 force fields were performed. All force fields yield sampled ensembles of conformations with collision cross sectional areas for the dimer that are statistically significantly larger than experimental results. All force fields, with the exception of AMBER-ff99sb-ILDN (8.8±6.4%) and CHARMM36 (2.7±4.2%), tend to overestimate the α-helical content compared to experimental CD (5.3±5.2%). Using the AMBER-ff99sb-NMR force field resulted in the greatest degree of variance (41.3±12.9%). Except for the AMBER-ff99sb-NMR force field, the others tended to under estimate the expected amount of β-sheet and over estimate the amount of turn/bend/random coil conformations. All force fields, with the exception AMBER-ff99sb-NMR, reproduce a theoretically expected β-sheet-turn-β-sheet conformational motif, however, only the CHARMM22* and CHARMM36 force fields yield results compatible with collapse of the central and C-terminal hydrophobic cores from residues 17-21 and 30-36. Although analyses of essential subspace sampling showed only minor variations between force fields, secondary structures of lowest energy conformers are different.
Gut microbiota has a widespread and modifiable effect on host gene regulation
Authors: Richards Allison L , Muehlbauer Amanda L , Alazizi Adnan , Burns Michael B , Findley Anthony , Messina Francesco , Gould Trevor J , Cascardo Camilla , Pique-Regi Roger , Blekhman Ran , Luca Francesca
Published: October 2017

Variation in gut microbiome is associated with wellness and disease in humans, yet the molecular mechanisms by which this variation affects the host are not well understood. A likely mechanism is through changing gene regulation in interfacing host epithelial cells. Here, we treated colonic epithelial cells with live microbiota from five healthy individuals and quantified induced changes in transcriptional regulation and chromatin accessibility in host cells. We identified over 5,000 host genes that change expression, including 588 distinct associations between specific taxa and host genes. The taxa with the strongest influence on gene expression alter the response of genes associated with complex traits. Using ATAC-seq, we show that a subset of these changes in gene expression are likely the result of changes in host chromatin accessibility and transcription factor binding induced by exposure to gut microbiota. We then created a manipulated microbial community with titrated doses ofCollinsella, demonstrating that both natural and controlled microbiome composition leads to distinct, and predictable, gene expression profiles in host cells. Together, our results suggest that specific microbes play an important role in regulating expression of individual host genes involved in human complex traits. The ability to fine tune the expression of host genes by manipulating the microbiome suggests future therapeutic routes.
Summarizing Performance for Genome Scale Measurement of miRNA: Reference Samples and Metrics
Authors: Pine PS , Lund SP , Parsons JR , Vang LK , Mahabal AA , Cinquini L , Kelly SC , Kincaid H , Crichton DJ , Spira A , Liu G , Gower AC , Pass HI , Goparaju C , Dubinett SM , Krysan K , Stass SA , Kukuruga D , Van Keuren-Jensen K , Courtright-Lim A , Thompson KL , Rosenzweig BA , Sorbara L , Srivastava S , Salit ML
Published: October 2017

Background

The potential utility of microRNA as biomarkers for early detection of cancer and other diseases is being investigated with genome-scale profiling of differentially expressed microRNA. Processes for measurement assurance are critical components of genome-scale measurements. Here, we evaluated the utility of a set of total RNA samples, designed with between-sample differences in the relative abundance of miRNAs, as process controls.

Results

Three pure total human RNA samples (brain, liver, and placenta) and two different mixtures of these components were evaluated as measurement assurance control samples on multiple measurement systems at multiple sites and over multiple rounds. In silico modeling of mixtures provided benchmark values for comparison with physical mixtures. Biomarker development laboratories using next-generation sequencing (NGS) or genome-scale hybridization assays participated in the study and returned data from the samples using their routine workflows. Multiplexed and single assay reverse-transcription PCR (RT-PCR) was used to confirm in silico predicted sample differences. Data visualizations and summary metrics for genome-scale miRNA profiling assessment were developed using this dataset, and a range of performance was observed. These metrics have been incorporated into an online data analysis pipeline and provide a convenient dashboard view of results from experiments following the described design. The website also serves as a repository for the accumulation of performance values providing new participants in the project an opportunity to learn what may be achievable with similar measurement processes.

Conclusions

The set of reference samples used in this study provides benchmark values suitable for assessing genome-scale miRNA profiling processes. Incorporation of these metrics into an online resource allows laboratories to periodically evaluate their performance and assess any changes introduced into their measurement process.
An evolutionary switch in the specificity of an endosomal CORVET tether underlies formation of regulated secretory vesicles in the ciliateTetrahymena thermophila
Authors: Sparvoli Daniela , Richardson Elisabeth , Osakada Hiroko , Lan Xun , Iwamoto Masaaki , Bowman Grant R. , Kontur Cassandra , Bourland William A. , Lynn Denis H. , Pritchard Jonathan K. , Haraguchi Tokuko , Dacks Joel B. , Turkewitz Aaron P.
Published: October 2017

In the endocytic pathway of animals, two related complexes, called CORVET (Class C Core Vacuole/Endosome Transport) and HOPS (Homotypic fusion and protein sorting), act as both tethers and fusion factors for early and late endosomes, respectively. Mutations in CORVET or HOPS lead to trafficking defects and contribute to human disease including immune dysfunction. HOPS and CORVET are conserved throughout eukaryotes but remarkably, in the ciliateTetrahymena thermophila,the HOPS-specific subunits are absent while CORVET-specific subunits have proliferated. VPS8 (Vacuolar Protein Sorting), a CORVET subunit, expanded to 6 paralogs inTetrahymena. This expansion correlated with loss of HOPS within a ciliate subgroup including the Oligohymenophorea, which containsTetrahymena. As uncovered via forward genetics, a singleVPS8paralog inTetrahymena(VPS8A) is required to synthesize prominent secretory granules called mucocysts. More specifically,∆vps8acells fail to deliver a subset of cargo proteins to developing mucocysts, instead accumulating that cargo in vesicles also bearing the mucocyst sorting receptor, Sor4p. Surprisingly, although this transport step relies on CORVET, it does not appear to involve early endosomes. Instead,Vps8aassociates with the late endosomal/lysosomal marker Rab7, indicating target specificity switching occurred in CORVET subunits during the evolution of ciliates. Mucocysts belong to a markedly diverse and understudied class of protist secretory organelles called extrusomes. Our results underscore that biogenesis of mucocysts depends on endolysosomal trafficking, revealing parallels with invasive organelles in apicomplexan parasites and suggesting that a wide array of secretory adaptations in protists, like in animals, depend on mechanisms related to lysosome biogenesis.

Abbreviations

LRO

(Lysosome-related organelle)

HOPS

(homotypic fusion and protein sorting complex)

CORVET

(Class C core Vacuole/Endosome Transport)

VPS

(vacuolar protein sorting)

GRL

(granule lattice)

GRT

(granule tip)

Igr

(Induced upon granule regeneration)

SNARE

(Soluble NSF attachment protein receptor)

LECA

(last eukaryotic common ancestor)
Computational Tools for the Identification and Interpretation of Sequence Motifs in Immunopeptidomes
Authors: Alvarez Bruno , Barra Carolina , Nielsen Morten , Andreatta Massimo
Published: October 2017

Recent advances in proteomics and mass-spectrometry have widely expanded the detectable peptide repertoire presented by major histocompatibility complex (MHC) molecules on the cell surface, collectively known as the immunopeptidome. Finely characterizing the immunopeptidome brings about important basic insights into the mechanisms of antigen presentation, but can also reveal promising targets for vaccine development and cancer immunotherapy. In this report, we describe a number of practical and efficient approaches to analyze immunopeptidomics data, discussing the identification of meaningful sequence motifs in various scenarios and considering current limitations. We address the issue of filtering false hits and contaminants, and the problem of motif deconvolution in cell lines expressing multiple MHC alleles, both for the MHC class I and class II systems. Finally, we demonstrate how machine learning can be readily employed by non-expert users to generate accurate prediction models directly from mass-spectrometry eluted ligand data sets.
Prophylactic vaccination protects against the development of oxycodone self-administration
Authors: Nguyen Jacques D. , Hwang Candy S. , Grant Yanabel , Janda Kim D. , Taffe Michael A.
Published: October 2017

Abuse of prescription opioids is a growing public health crisis in the United States, with drug overdose deaths increasing dramatically over the past 15 years. Few preclinical studies exist on the reinforcing effects of oxycodone or on the development of therapies for oxycodone abuse. This study was conducted to determine if immunopharmacotherapy directed against oxycodone would be capable of altering oxycodone-induced antinociception and intravenous self-administration. Male Wistar rats were administered a small-molecule immunoconjugate vaccine (Oxy-TT) or the control carrier protein, tetanus toxoid (TT), and trained to intravenously self-administer oxycodone (0.06 or 0.15 mg/kg/infusion). Brain oxycodone concentrations were 50% lower in Oxy-TT rats compared to TT rats 30 minutes after injection (1 mg/kg, s.c.) whereas plasma oxycodone was 15-fold higher from drug sequestration by circulating antibodies. Oxy-TT rats were also less sensitive to 1–2 mg/kg, s.c. oxycodone on a hot water nociception assay. Half of the Oxy-TT rats failed to acquire intravenous self-administration under the 0.06 mg/kg/infusion training dose. Oxycodone self-administration of Oxy-TT rats trained on 0.15 mg/kg/infusion was higher than controls; however under progressive ratio (PR) conditions the Oxy-TT rats decreased their oxycodone intake, unlike TT controls. These data demonstrate that active vaccination provides protection against the reinforcing effects of oxycodone. Anti-oxycodone vaccines may entirely prevent repeated use in some individuals who otherwise would become addicted. Vaccination may also reduce dependence in those who become addicted and therefore facilitate the effects of other therapeutic interventions which either increase the difficulty of drug use or incentivize other behaviors.
Variation in context dependent foraging behavior across pollinators
Authors: Briggs Heather M. , Graham Stuart , Switzer Callin M. , Hopkins Robin
Published: October 2017

Pollinator foraging behavior has direct consequences for plant reproduction and has been implicated in driving floral trait evolution. Exploring the degree to which pollinators exhibit flexibility in foraging behavior will add to a mechanistic understanding of how pollinators can impact selection on plant traits. Although plants have evolved suites of floral traits to attract pollinators, flower color is a particularly important aspect of the floral display. Some pollinators show strong innate color preference, but many pollinators display flexibility in preference due to learning associations between rewards and color, or due to variable perception of color in different environments or plant communities. This study examines the flexibility in flower color preference of two groups of native butterfly pollinators under natural field conditions. Our study reveals that pipevine swallowtails and skippers, the predominate pollinators of the two native Texas Phlox species, display distinct patterns of color preferences across different contexts. Pipevine swallowtails exhibit highly flexible color preferences and likely utilize other floral traits to make foraging decisions. In contrast, skippers have consistent color preferences and likely use flower color as a primary cue for foraging. As a result of this variation in color preference flexibility, the two pollinator groups impose concordant selection on flower color in some contexts but discordant selection in other contexts. This variability could have profound implications for how flower traits respond to pollinator-mediated selection. Our findings suggest that studying dynamics of behavior in natural field conditions is important for understanding plant-pollinator interactions.
Effects of mRNA degradation and site-specific transcriptional pausing on protein expression noise
Authors: Kim Sangjin , Jacobs-Wagner Christine
Published: October 2017

Genetically identical cells exhibit diverse phenotypes, even when experiencing the same environment. This phenomenon, in part, originates from cell-to-cell variability (noise) in protein expression. While various kinetic schemes of stochastic transcription initiation are known to affect gene expression noise, how post-transcription initiation events contribute to noise at the protein level remains incompletely understood. To address this question, we developed a stochastic simulation-based model of bacterial gene expression that integrates well-known dependencies between transcription initiation, transcription elongation dynamics, mRNA degradation and translation. We identified realistic conditions under which mRNA lifetime and transcriptional pauses modulate the protein expression noise initially introduced by the promoter architecture. For instance, we found that the short lifetime of bacterial mRNAs facilitates the production of protein bursts. Conversely, RNA polymerase (RNAP) pausing at specific sites during transcription elongation can attenuate protein bursts by fluidizing the RNAP traffic to the point of erasing the effect of a bursty promoter. Pause-prone sites, if located close to the promoter, can also affect noise indirectly by reducing both transcription and translation initiation due to RNAP and ribosome congestion. Our findings highlight how the interplay between transcription initiation, transcription elongation, translation and mRNA degradation shapes the distribution in protein numbers. They also have implications for our understanding of gene evolution and suggest combinatorial strategies for modulating phenotypic variability by genetic engineering.
RACIPE: A computational tool for Modeling Gene Regulatory Circuits using Randomization
Authors: Huang Bin , Jia Dongya , Feng Jingchen , Levine Herbert , Onuchic José N. , Lu Mingyang
Published: October 2017

Motivation

One of the major challenges in traditional mathematical modeling of gene regulatory circuits is the insufficient knowledge of kinetic parameters. These parameters are often inferred from existing experimental data and/or educated guesses, which can be time-consuming and error-prone, especially for large networks.

Results

We present a computational tool based on our newly developed method named random circuit perturbation (RACIPE), to explore the robust dynamical features of gene regulatory circuits without the requirement of detailed kinetic parameters. RACIPE generates an ensemble of circuit models with distinct random parameters and uniquely identifies robust dynamical properties by statistical analysis. Here, we discuss software implementation and illustrate the usage of RACIPE on coupled toggle-switch circuits and a published circuit of B-lymphopoiesis. We expect RACIPE to contribute to a more comprehensive and unbiased understanding of gene regulatory mechanisms.

Availability

RACIPE is a free open source software distributed under (Apache 2.0) license and can be downloaded from GitHub (https://github.com/simonhb1990/RACIPE-1.0).

Contact

Mingyang.Lu@jax.org, Herbert.Levine@rice.edu or jonuchic@rice.edu
Comparative Analysis of Gene Expression Identifies Distinct Molecular Signatures of Bone Marrow- and Periosteal-Skeletal Stem/Progenitor Cells
Authors: Deveza Lorenzo , Ortinau Laura , Lei Kevin , Park Dongsu
Published: October 2017

Periosteum and bone marrow (BM) both contain skeletal stem/progenitor cells (SSCs) that participate in fracture repair. However, the functional difference and selective regulatory mechanisms of SSCs in different location are unknown due to the lack of specific markers. Here, we report a comprehensive gene expression analysis of bone marrow SSCs (BM-SSCs), periosteal SSCs (P-SSCs), and more differentiated osteoprogenitors by using reporter mice expressing Interferon-inducible Mx1 and NestinGFP, previously known SSC markers. We first defined that the BM-SSCs can be enriched by the combination of Mx1 and NestinGFP expression, while endogenous P-SSCs can be isolated by positive selection of Mx1, CD105 and CD140a (known SSC markers) combined with the negative selection of CD45, CD31, and osteocalcinGFP (a mature osteolineage marker). Comparative gene experession analysis with FACS-sorted BM-SSCs, P-SSCs, Osterix+ (OSX) preosteoblasts, CD51+ stroma cells and CD45+ hematopoietic cells as controls revealed that BM-SSCs and P-SSCs have high similarity with few potential differences without statistical significance. We also found that CD51+ cells are highly heterogeneous and little overlap with SSCs. This was further supported by the microarray cluster analysis, and the two populations clustered together. However, when comparing SSC population to controls, we found several genes that were uniquely upregulated in endogenous SSCs. Amongst these genes, we found KDR (aka Flk1 or VEGFR2) to be most interesting and discovered that it is highly and selectively expressed in P-SSCs. This finding suggests that endogenous P-SSCs are functionally very similar to BM-SSCs with undetectable significant differences in gene expression but there are distinct molecular signatures in P-SSCs, which can be useful to specify P-SSC subset in vivo.
Stochastic character mapping of state-dependent diversification reveals the tempo of evolutionary decline in self-compatible Onagraceae lineages
Authors: Freyman William A. , Höhna Sebastian
Published: October 2017

A major goal of evolutionary biology is to identify key evolutionary transitions that correspond with shifts in speciation and extinction rates. Stochastic character mapping has become the primary method used to infer the timing, nature, and number of character state transitions along the branches of a phylogeny. The method is widely employed for standard substitution models of character evolution. However, current approaches cannot be used for models that specifically test the association of character state transitions with shifts in diversification rates such as state-dependent speciation and extinction (SSE) models. Here we introduce a new stochastic character mapping algorithm that overcomes these limitations, and apply it to study mating system evolution over a time-calibrated phylogeny of the plant family Onagraceae. Utilizing a hidden state SSE model we tested the association of the loss of self-incompatibility with shifts in diversification rates. We found that self-compatible lineages have higher extinction rates and lower net-diversification rates compared to self-incompatible lineages. Furthermore, these results provide empirical evidence for the “senescing” diversification rates predicted in highly selfing lineages: our mapped character histories show that the loss of self-incompatibility is followed by a short-term spike in speciation rates, which declines after a time lag of several million years resulting in negative net-diversification. Lineages that have long been self-compatible, such as Fuchsia and Clarkia, are in a previously unrecognized and ongoing evolutionary decline. Our results demonstrate that stochastic character mapping of SSE models is a powerful tool for examining the timing and nature of both character state transitions and shifts in diversification rates over the phylogeny.
Combinatorial Drug Discovery in Nanoliter Droplets
Authors: Kulesa Anthony , Kehe Jared , Hurtado Juan , Tawde Prianca , Blainey Paul C.
Published: October 2017

Combinatorial drug treatment strategies perturb biological networks synergistically to achieve therapeutic effects and represent major opportunities to develop advanced treatments across a variety of human disease areas. However, the discovery of new combinatorial treatments is challenged by the sheer scale of combinatorial chemical space. Here we report a high-throughput system for nanoliter-scale phenotypic screening that stabilizes a chemical library in nanoliter droplet emulsions and automates the formulation of chemical combinationsen massusing parallel droplet processing. We apply this system to predict synergy between more than 4,000 investigational and approved drugs and a panel of 10 antibiotics againstE. coli, a model Gram-negative pathogen. We found a range of drugs not previously indicated for infectious disease that synergize with antibiotics. Our validated hits include drugs that synergize with the antibiotics vancomycin, erythromycin, and novobiocin, which are used against Gram-positive bacteria but are not effective by themselves to resolve Gram-negative infections.
The Association of Externalizing and Internalizing Problems with Indicators of Intelligence in a Sample of At-Risk Children
Authors: Kavish Nicholas , Helton Jesse , Vaughn Michael G. , Boutwell Brian B.
Published: October 2017

To date, a substantial body of research exists suggesting an association between indicators of intelligence and various deleterious outcomes, including externalizing and internalizing behavioral problems. Much of this research, however, has focused on samples drawn from the general population, thus it remains less clear how (and if) intelligence relates to problem behaviors in samples of highly at-risk individuals. The current study seeks to contribute to this knowledge base by examining the associations between intelligence and internalizing, externalizing, and total scores on the Child Behavioral Checklist in a sample of approximately 2,500 highly disadvantaged respondents considered by Child Protective Services as at-risk for abuse or neglect. While the two measures of intelligence performed differently, there emerged some association between overall lower IQ and higher total behavioral problem scores. There was some evidence that low IQ also predicted higher internalizing scores, but this relationship varied greatly by measure and model. Results, limitations, and implications of the current study are discussed.
Distinct stimulatory mechanisms regulate the catalytic activity of Polycomb Repressive Complex 2 (PRC2)
Authors: Lee Chul-Hwan , Holder Marlene , Grau Daniel , Saldana-Meyer Ricardo , Ganai Rais Ahmad , Zhang Jenny , Wang Miao , Dobenecker Marc-Werner , Reinberg Danny , Armache Karim-Jean
Published: October 2017

The maintenance of gene expression patterns during metazoan development is carried out, in part, by the actions of the Polycomb Repressive Complex 2 (PRC2). PRC2 catalyzes mono-, di-and trimethylation of histone H3 at lysine 27 (H3K27), with H3K27me2/3 being strongly associated with silenced genes. We demonstrate that EZH1 and EZH2, the two mutually exclusive catalytic subunits of PRC2, are differentially activated by various mechanisms. While both PRC2-EZH1 and PRC2-EZH2 are able to catalyze monomethylation, only PRC2-EZH2 is strongly activated by allosteric modulators and specific chromatin substrates to catalyze di-and trimethylation of H3K27. However, we also show that a PRC2 associated protein, AEBP2, can stimulate the activity of both complexes through a mechanism independent of and additive to allosteric activation. These results have strong implications regarding the cellular requirements for and accompanying adjustments in PRC2 activity, given the difference in the expression of EZH1 and EZH2 upon cellular differentiation.
Rolling a mycobiome down a hill: endophytes in the Taiwanese Cloud Forest
Authors: Thomas Dan , Vandegrift Roo , Ju Yu-Ming , Hsieh Monica , Roy Bitty
Published: October 2017

Fungal endophytes of plants are ubiquitous and important to host plant health. Despite their ecological importance, landscape-level patterns of microbial communities in plant hosts are not well-characterized. Fungal wood-inhabiting and foliar endophyte communities from multiple tree hosts were sampled at multiple spatial scales across a 25 ha subtropical research plot in northern Taiwan, using culture-free, community DNA amplicon sequencing methods. Fungal endophyte communities were distinct between leaves and wood, but the mycobiomes were highly variable across and within tree species. Of the variance that could be explained, host tree species was the most important driver of mycobiome community-composition. Within a single tree species, “core” mycobiomes were characterized using cooccurrence analysis. These core groups of endophytes in leaves and wood show divergent spatial patterns. For wood endophytes, a more consistent, “minimal” core mycobiome coexisted with the host across the extent of the study. For leaf endophytes, the core fungi resembled a more dynamic, “gradient” model of the core microbiome, changing across the topography and distance of the study.