bluuebunny/crossref_metadata_2025 huggingface dataset:
Intercontinental genomic parallelism in multiple adaptive radiations
Authors: Magalhaes Isabel S. , Whiting James R. , D’Agostino Daniele , Hohenlohe Paul A. , Mahmud Muayad , Bell Michael A. , Skúlason Skúli , MacColl Andrew D.C.
Published: December 2019

Parallelism, the evolution of similar traits in populations diversifying in similar conditions, provides good evidence of adaptation by natural selection. Many studies of parallelism have focused on comparisons of strongly different ecotypes or sharply contrasting environments, defineda priori, which could upwardly bias the apparent prevalence of parallelism. Here, we estimated genomic parallelism associated with individual components of environmental and phenotypic variation at an intercontinental scale across four adaptive radiations of the three-spined stickleback (Gasterosteus aculeatus), by associating genome-wide allele frequencies with continuous distributions of environmental and phenotypic variation. We found that genomic parallelism was well predicted by parallelism of phenotype-environment associations, suggesting that a quantitative characterization of phenotypes and environments can provide a good prediction of expected genomic parallelism. Further, we examined the explanatory power of genetic, phenotypic, and environmental similarity in predicting parallelism. We found that parallelism tended to be greater for geographically proximate, genetically similar radiations, highlighting the significant contingency of standing variation in the early stages of adaptive radiations, before new mutations accumulate. However, we also demonstrate that distance within multivariate environmental space predicts parallelism, after correction for genetic distance. This study thus demonstrates the relative influences of environment, phenotype and genetic contingency on repeatable signatures of adaptation in the genome.
Changing environments reveal innovative genetic variation in children’s cortisol responses
Authors: Raffington Laurel , Malanchini Margherita , Grotzinger Andrew D. , Madole James W. , Engelhardt Laura E. , Sabhlok Aditi , Youn Cherry , Patterson Megan W. , Harden K. Paige , Tucker-Drob Elliot M.
Published: December 2019

Genetic associations with biopsychosocial phenotypes are often interpreted as evidence that the genome codes for fixed end-states. Instead, a given genotype might regulate a dynamic range of phenotypes in response to environmental change. We collected hair cortisol (n = 1,104), salivary cortisol in reaction to an in-laboratory stressor (n = 537), and diurnal salivary cortisol (n = 488) from twins aged 8-15 years in the Texas Twin Project. Baseline genetic variation in both salivary and hair cortisol was not simply magnified after stressor exposure or after waking. Rather, novel genetic influences on cortisol arose over time. Thus, environmental change can reveal genetic variation that would not otherwise be observed in static cortisol levels. These findings are in line with the notion that the genome regulates individuals’ reactions to the environment that differ across environments.
Kidney Function and Blood Pressure: A Bi-directional Mendelian Randomisation Study
Authors: Yu Zhi , Coresh Josef , Qi Guanghao , Grams Morgan , Boerwinkle Eric , Snieder Harold , Teumer Alexander , Pattaro Cristian , Köttgen Anna , Chatterjee Nilanjan , Tin Adrienne
Published: December 2019

Objective

To evaluate the bi-directional causal relation between kidney function and blood pressure.

Design

Mendelian randomisation study.

Setting

We performed two-sample Mendelian randomisation analyses. Genetic instruments of kidney function traits were selected from summary statistics of genome-wide association studies (GWAS) of glomerular filtration rate estimated from serum creatinine (eGFRcr) and blood urea nitrogen (BUN) and were required to be associated with both eGFRcr and BUN to ensure that the instruments were more likely to represent the underlying kidney function. Genetic instruments of blood pressure were selected from summary statistics of GWAS of systolic and diastolic blood pressure. We investigated Mendelian randomisation hypothesis using several alternative approaches, including methods that are most robust to the presence of horizontal pleiotropy.

Participants

The summary statistics of eGFRcr included 567,460 participants from 54 cohorts, and the summary statistics of BUN included 243,031 participants from 48 cohorts from the Chronic Kidney Disease Genetics (CKDGen) Consortium. The summary statistics of systolic and diastolic blood pressure included 757,601 participants from the UK Biobank and 78 cohorts from the International Consortium for Blood Pressure (ICBP).

Results

Significant evidence supported the causal effects of higher kidney function on lower blood pressure with multiple methods. Based on the mode-based Mendelian randomisation analysis approach, known for its robustness to the presence of pleiotropic effect, the effect estimate for 1 SD higher in eGFRcr was −0.17 SD unit (95 % CI: −0.09 to −0.24) in systolic blood pressure (SBP) and −0.15 SD unit (95% CI: −0.07 to −0.22) in diastolic blood pressure (DBP). In contrast, the causal effects of blood pressure on kidney function were not statistically significant.

Conclusions

Mendelian randomisation analyses support causal effects of higher kidney function on lower blood pressure. These results suggest preventing kidney function decline can reduce the public health burden of hypertension.
Global analysis of adenylate-forming enzymes reveals β-lactone biosynthesis pathway in pathogenicNocardia
Authors: Robinson Serina L. , Terlouw Barbara R. , Smith Megan D. , Pidot Sacha J. , Stinear Tim P. , Medema Marnix H. , Wackett Lawrence P.
Published: December 2019

Enzymes that cleave ATP to activate carboxylic acids play essential roles in primary and secondary metabolism in all domains of life. Class I adenylate-forming enzymes share a conserved structural fold but act on a wide range of substrates to catalyze reactions involved in bioluminescence, nonribosomal peptide biosynthesis, fatty acid activation, and β-lactone formation. Despite their metabolic importance, the substrates and catalytic functions of the vast majority of adenylate-forming enzymes are unknown without tools available to accurately predict them. Given the crucial roles of adenylate-forming enzymes in biosynthesis, this also severely limits our ability to predict natural product structures from biosynthetic gene clusters. Here we used machine learning to predict adenylate-forming enzyme function and substrate specificity from protein sequence. We built a web-based predictive tool and used it to comprehensively map the biochemical diversity of adenylate-forming enzymes across >50,000 candidate biosynthetic gene clusters in bacterial, fungal, and plant genomes. Ancestral enzyme reconstruction and sequence similarity networking revealed a ‘hub’ topology suggesting radial divergence of the adenylate-forming superfamily from a core enzyme scaffold most related to contemporary aryl-CoA ligases. Our classifier also predicted β-lactone synthetases in novel biosynthetic gene clusters conserved across >90 different strains ofNocardia. To test our computational predictions, we purified a candidate β-lactone synthetase fromNocardia brasiliensisand reconstituted the biosynthetic pathwayin vitroto link the gene cluster to the β-lactone natural product, nocardiolactone. We anticipate our machine learning approach will aid in functional classification of enzymes and advance natural product discovery.
Top predator introduction changes the effects of spatial isolation on freshwater community structure
Authors: Pelinson Rodolfo Mei , Leibold Mathew A. , Schiesari Luis
Published: December 2019

The importance of local selective pressures on community structure is predicted to increase with spatial isolation when species favored by local conditions also have higher dispersal rates. In freshwater habitats, the introduction of predatory fish can produce trophic cascades because fish tend to prey upon intermediate predatory taxa, such as predatory insects, which indirectly benefits herbivores and detritivores. Similarly, spatial isolation is known to limit predatory insect's colonization rates more strongly than of herbivores and detritivores, thus generating similar effects. Here we tested the hypothesis that the effect of introduced predatory fish on macroinvertebrate community structure increases across a gradient of spatial isolation by conducting a field experiment where artificial ponds with and without fish (the Redbreast Tilapia) were constructed at three different distances from a source wetland. Overall results show that fish do reduce the abundance of predatory insects but have no effect on the abundance of herbivores and detritivores. Spatial isolation, however, does strengthen the trophic cascade caused by dispersal limitation of predatory insects, but only in the absence of fish. More importantly, macroinvertebrate communities with and without fish tend to diverge more strongly at higher spatial isolation, however, this pattern was not due to an increase in the magnitude of the effect of fish, as initially hypothesized, but to a change in the effect of isolation in the presence of fish. We argue that as spatial isolation increases, suitable prey, such as predatory insects become scarce and fish increases predation pressure upon herbivores and detritivores, dampening the positive effect of spatial isolation on them. Our results highlight the importance of considering interspecific variation in dispersal and multiple trophic levels to better understand the processes generating metacommunity structures.
Integration of absolute multi-omics reveals translational and metabolic interplay in mixed-kingdom microbiomes
Authors: Delogu F. , Kunath B.J. , Arntzen M.Ø. , Hvidsten T.R. , Pope P.B.
Published: December 2019

Microbiology is founded on well-known model organisms. For example, the majority of our fundamental knowledge regarding the quantitative levels of DNA, RNA, and protein backdates to keystone pure culture-based studies. Nowadays, meta-omic approaches allow us to directly access the molecules that constitute microbes and microbial communities, however due to a lack of absolute measurements, many original culture-derived “microbiology statutes” have not been updated or adapted to more complex microbiome settings. Within a cellulose-degrading and methanogenic consortium, we temporally measured genome-centric absolute RNA and protein levels per gene, and obtained a protein-to-RNA ratio of 102-104 for bacterial populations, whereas Archaeal RNA/protein dynamics (103-105: Methanothermobacter thermoautotrophicus) were more comparable to Eukaryotic representatives humans and yeast. The linearity between transcriptome and proteome had a population-specific change over time, highlighting a minimal subset of four functional carriers (cellulose degrader, fermenter, syntrophic acetate-oxidizer and methanogen) that coordinated their respective metabolisms, cumulating in the overarching community phenotype of converting polysaccharides to methane. Our findings show that upgrading multi-omic toolkits with traditional absolute measurements unlocks the scaling of core biological questions to dynamic and complex microbiomes, creating a deeper insight into inter-organismal relationships that drive the greater community function.
Skap2 Regulates Atherosclerosis through Macrophage Polarization and Efferocytosis
Authors: Hyatt Danielle , Schroeder Allison E. , Bhatnagar Ashita , Golan David E. , Swanson Kenneth D. , Alenghat Francis J.
Published: December 2019

Rationale

Atherosclerosis causes more deaths than any other pathophysiologic process. It has a well-established inflammatory, macrophage-mediated component, but important and potentially protective intracellular macrophage processes in atherosclerosis remain enigmatic. Src Kinase-Associated Phosphoprotein 2 (Skap2) is a macrophage-predominant adaptor protein critical for cytoskeletal reorganization, and thereby, for macrophage migration and chemotaxis. The role of macrophage Skap2 in atherosclerosis is unknown and deserves exploration.

Objective

To establish the critical role of Skap2 in macrophage-mediated atherosclerotic plaque homeostasis.

Results

In human arterial gene expression analysis, Skap2 expression is enriched in macrophage-containing areas of human atheroma, and the transcript level varies with plaque characteristics. We have discovered that deletion of Skap2 accelerates atherosclerosis by threefold in ApoE-/- mice on standard diet. Skap2 expression is switched on only as monocytes differentiate into macrophages, so Skap2-/- monocytes have no defect in infiltrating the atheroma. On the other hand, once they fully differentiate, Skap2-deficient macrophages cannot polarize efficiently into alternatively-activated, regulatory cells, and instead they preferentially polarize toward the classical pro-inflammatory phenotype both ex vivo and within the developing atheroma. This defect extends to polarized effector functions, as ex vivo analysis of macrophage phagocytosis of dying foam cells indicates that Skap2 is required for the regulatory process of efferocytosis.

Conclusions

Taken together, our findings support a model in which Skap2 drives a regulatory, efferocytic mode of behavior to quell atherosclerosis.

CONDENSED ABSTRACT / SUMMARY

Skap2—a macrophage protein found in the human atheroma—is atheroprotective. Skap2-null mice, whose foam cells do not migrate well due to a defect in integrin-induced cytoskeletal rearrangement, have accelerated atherosclerosis. Skap2 is not expressed in monocytes but becomes important once they reach the atheroma and become macrophage foam cells, at which point it drives toward a regulatory, anti-inflammatory polarization state required for efficient efferocytosis of dying foam cells. Thus, Skap2 drives a protective, regulatory mode of behavior, supporting the fact that macrophages are not solely deleterious in atherosclerosis, and further pointing to efferocytosis as a target for therapy.

There are no relationships to disclose.
CofActor: A light and redox-gated optogenetic clustering tool to study abnormal cytoskeletal dynamics in stressed cells
Authors: Salem Fatema B. , Prabhu V. V. , Kuyateh Abu-Bakarr , Bunner Wyatt Paul , Murashov Alexander , Szatmari Erzsebet M. , Hughes Robert M.
Published: December 2019

The biochemical hallmarks of neurodegenerative diseases (neural fibrils, clumps, and tangles; heightened reactive oxygen species (ROS); cofilin-actin rods) have presented numerous challenges for development of in vivo diagnostic tools (1–7). Biomarkers such as amyloid beta (Aβ) fibrils and Tau tangles in Alzheimer’s Disease (AD) are only accessible via invasive cerebrospinal fluid assay for peptide mass fingerprinting or post-mortem diagnosis (8–11), while ROS can be fleeting and thus challenging to monitor in vivo (12–15). While remaining a challenge for in vivo detection, the unique protein-protein interactions underlying these disease-specific biomarkers also present rich opportunities for the engineering of in vitro pathology-sensitive biosensors and bioactuators. These tools can be useful for the investigation of critical, early stage events in neurodegenerative diseases in both cellular and animal models (16, 17), while potentially leading to advanced detection reagents with clinical applications. In this report, we describe a light and redox-gated protein switch inspired by the phenomenon of cofilin-actin rod formation, which occurs in stressed neurons in the AD brain and following brain ischemia (18). By coupling the redox-sensitive interaction of cofilin and actin with the light responsive Cry2-CIB blue light switch, we accomplish both light- and ROS-gated control of this interaction. The resulting switch is referred to as the “CofActor” system. Site-directed mutagenesis of both cofilin and actin partners demonstrate which residues are critical for sustaining or abrogating the light and redox gated response. Furthermore, switch response varies depending on whether oxidative stress is generated via glycolytic inhibition or a combination of glycolytic inhibition and azide-induced oxidative stress. Finally, light and redox gated switch function was demonstrated in cultured hippocampal neurons. As a dual input biosensor, CofActor holds promise for the tracking of early stage events in neurodegeneration and the investigation of actin-binding protein interactions under oxidative stress.
Differential efficacies of Cas nucleases on microsatellites involved in human disorders and associated off-target mutations
Authors: Poggi Lucie , Emmenegger Lisa , Descorps-Declère Stéphane , Dumas Bruno , Richard Guy-Franck
Published: December 2019

Microsatellite expansions are the cause of more than 20 neurological or developmental human disorders. Shortening expanded repeats using specific DNA endonucleases may be envisioned as a gene editing approach. Here, a new assay was developed to test several CRISPR-Cas nucleases on microsatellites involved in human diseases, by measuring at the same time double-strand break rates, DNA end resection and homologous recombination efficacy. Broad variations in nuclease performances were detected on all repeat tracts.Streptococcus pyogenesCas9 was the most efficient of all. All repeat tracts did inhibit double-strand break resection. We demonstrate that secondary structure formation on the guide RNA was a major determinant of nuclease efficacy. Using deep sequencing, off-target mutations were assessed genomewide. Out of 221 CAG/CTG or GAA/TTC trinucleotide repeats of the yeast genome, three were identified as carrying statistically significant low frequency mutations, corresponding to off-target effects.
The rate of de novo CNVs in healthy controls
Authors: Barone Jacopo , Smith Mathew , Kendall Kimberley , Owen Michael J , O’Donovan Michael C , Kirov George
Published: December 2019

Background

Copy number variation (CNV) is an important cause for human disease. Due to relatively high selection pressure operating against pathogenic CNVs, their rate is maintained in the population by de novo formation. The rates of de novo CNVs are increased in neurodevelopmental disorders. However only a few studies have been performed on relatively healthy individuals, making it problematic to calculate the magnitude of this increased rate.

Methods

The UK Biobank recruited about half a million randomly selected middle-aged members of the general population of the UK. We re-constructed family relationships from the genotypic data and identified 923 parent-offspring trios that passed out quality control filters. Potential de novo CNVs of >100 kb in size were identified and the log R ratios (LRR) and B allele frequency (BAF) traces of the trio members were visually inspected for those regions. We had no opportunity to validate CNVs with a laboratory method, but the traces appeared conclusive.

Results and Discussion

We identified 10 CNVs >100kb in size, a rate of 1.1%. These rates are very similar to those in previous large studies. Using previous large studies, we provide overall rates among 4844 trios for different size ranges that are expected in relatively healthy populations. These rates can be used for comparison in studies on disease populations.
The Role of Scale in the Estimation of Cell-type Proportions
Authors: Hunt Gregory J. , Gagnon-Bartsch Johann A.
Published: December 2019

Complex tissues are composed of a large number of different types of cells, each involved in a multitude of biological processes. Consequently, an important component to understanding such processes is understanding the cell-type composition of the tissues. Estimating cell type composition using high-throughput gene expression data is known as cell-type deconvolution. In this paper, we first summarize the extensive deconvolution literature by identifying a common regression-like approach to deconvolution. We call this approach the Unified Deconvolution-as-Regression (UDAR) framework. While methods that fall under this framework all use a similar model, they fit using data on different scales. Two popular scales for gene expression data are logarithmic and linear. Unfortunately, each of these scales has problems in the UDAR framework. Using log-scale gene expressions proposes a biologically implausible model and using linear-scale gene expressions will lead to statistically inefficient estimators. To overcome these problems, we propose a new approach for cell-type deconvolution that works on a hybrid of the two scales. This new approach is biologically plausible and improves statistical efficiency. We compare the hybrid approach to other methods on simulations as well as a collection of eleven real benchmark datasets. Here, we find the hybrid approach to be accurate and robust.deconvolution, gene expression, microarray, RNA-seq
PhenoMIP: High Throughput Phenotyping of Diverse C. elegans Populations via Molecular Inversion Probes
Authors: Mok Calvin , Belmarez Gabriella , Edgley Mark L. , Moerman Donald G. , Waterston Robert H.
Published: December 2019

Whether generated within a lab setting or isolated from the wild, variant alleles continue to be an important resource for decoding gene function in model organisms such as Caenorhabditis elegans. With advances in massively parallel sequencing, multiple whole-genome sequenced (WGS) strain collections are now available to the research community. The Million Mutation Project (MMP) for instance, analysed 2007 N2-derived, mutagenized strains. Individually, each strain averages ∼400 single nucleotide variants amounting to ∼80 protein coding variants. The effects of these variants, however, remain largely uncharacterized and querying the breadth of these strains for phenotypic changes requires a method amenable to rapid and sensitive high-throughput analysis. Here we present a pooled competitive fitness approach to quantitatively phenotype subpopulations of sequenced collections via molecular inversion probes (PhenoMIP). We phenotyped the relative fitness of 217 mutant strains on multiple food sources and classified these into five categories. We also demonstrate on a subset of these strains, that their fitness defects can be genetically mapped. Overall, our results suggest that approximately 80% of MMP mutant strains may have a decreased fitness relative to the lab reference, N2. The costs of generating this form of analysis through WGS methods would be prohibitive while PhenoMIP analysis in this manner is accomplished at less than 1% of projected WGS costs. We propose methods for applying PhenoMIP to a broad range of population selection experiments in a cost-efficient manner that would be useful to the community at large.
Brain DNA Methylation Patterns in CLDN5 Associated With Cognitive Decline
Authors: Hüls Anke , Robins Chloe , Conneely Karen N. , Edgar Rachel , De Jager Philip L. , Bennett David A. , Wingo Aliza P. , Epstein Michael P. , Wingo Thomas S.
Published: December 2019

Objective

Cognitive decline is a hallmark of dementia; however, the brain epigenetic signature of cognitive decline is unclear. We investigated the associations between brain tissue-based DNA methylation and cognitive trajectory.

Methods

We performed a brain epigenome-wide association study of cognitive trajectory in 636 participants from the Religious Order Study and the Rush Memory and Aging Project (ROS/MAP) using DNA methylation profiles of the dorsal lateral prefrontal cortex (dPFC). To maximize our power to detect epigenetic associations, we used the recently developed Gene Association with Multiple Traits (GAMuT) test to analyze the five measured cognitive domains simultaneously.

Results

We found an epigenome-wide association for differential methylation of sites in the Claudin-5 (CLDN5) locus and cognitive trajectory (p-value x 9.96 × 10-7), which was robust to adjustment for cell type proportions (p-value = 8.52 x 10-7). This association was primarily driven by association with declines in episodic (p-value = 4.65 x 10-6) and working memory (p-value = 2.54 x 10-7). This association between methylation in CLDN5 and cognitive decline was independent of beta-amyloid and neurofibrillary tangle pathology and present in participants with low levels of neuropathology. In addition, only 13-31% of the association between methylation and cognitive decline was mediated through levels of neuropathology, whereas the major part of the association was independent of it.

Interpretation

We identified methylation in CLDN5 as new epigenetic factor associated with cognitive trajectory. Higher levels of methylation in CLDN5 were associated with faster cognitive decline implicating the blood brain barrier in maintenance of cognitive trajectory.
Polygenic risk of psychiatric disorders exhibits cross-trait associations in electronic health record data
Authors: Kember Rachel L. , Merikangas Alison K. , Verma Shefali S. , Verma Anurag , Judy Renae ,   Regeneron Genetics Center, Damrauer Scott M. , Ritchie Marylyn D. , Rader Daniel J. , Bućan Maja
Published: December 2019

Objective

Prediction of disease risk is a key component of precision medicine. Common, complex traits such as psychiatric disorders have a complex polygenic architecture making the identification of a single risk predictor difficult. Polygenic risk scores (PRS) denoting the sum of an individual’s genetic liability for a disorder are a promising biomarker for psychiatric disorders, but require evaluation in a clinical setting.

Methods

We develop PRS for six psychiatric disorders (schizophrenia, bipolar disorder, major depressive disorder, cross disorder, attention-deficit/hyperactivity disorder, anorexia nervosa) and 17 non-psychiatric traits in over 10,000 individuals from the Penn Medicine Biobank with accompanying electronic health records. We perform phenome-wide association analyses to test their association across disease categories.

Results

Four of the six psychiatric PRS were associated with their primary phenotypes (odds ratios between 1.2-1.6). Individuals in the highest quintile of risk had between 1.4-2.9 times higher odds of the disorder than the remaining 80% of individuals. Cross-trait associations were identified both within the psychiatric domain and across trait domains. PRS for coronary artery disease and years of education were significantly associated with psychiatric disorders, largely driven by an association with tobacco use disorder.

Conclusions

We demonstrate that the genetic architecture of common psychiatric disorders identified in a clinical setting confirms that which has been derived from large consortia. Even though the risk associated is low in this context, these results suggest that as identification of genetic markers proceeds, PRS is a promising approach for prediction of psychiatric disorders and associated conditions in clinical registries.
Sequencing Chemically Induced Mutations in the Mutamouse Lacz Reporter Gene Identifies Human Cancer Mutational Signatures
Authors: Beal Marc A. , Meier Matt J. , LeBlanc Danielle , Maurice Clotilde , O’Brien Jason , Yauk Carole L. , Marchetti Francesco
Published: December 2019

Transgenic rodent (TGR) models use bacterial reporter genes to quantifyin vivomutagenesis. Pairing TGR assays with next-generation sequencing (NGS) enables comprehensive mutation spectrum analysis to inform mutational mechanisms. We used this approach to identify 2,751 independentlacZmutations in the bone marrow of MutaMouse animals exposed to four chemical mutagens: benzo[a]pyrene,N-ethyl-N-nitrosourea, procarbazine, and triethylenemelamine. We also collected published data for 706lacZmutations from eight additional environmental mutagens. We demonstrate thatlacZgene sequencing generates chemical-specific mutation signatures observed in human cancers with established environmental causes. For example, the mutation signature of benzo[a]pyrene, a potent carcinogen in tobacco smoke, matched the signature associated with tobacco-induced lung cancers. Our results show that the analysis of chemically induced mutations in thelacZgene shortly after exposure provides an effective approach to characterize human-relevant mechanisms of carcinogenesis and identify novel environmental causes of mutation signatures observed in human cancers.
Developmental plasticity ofBrachypodium distachyonin response to P deficiency: modulation by inoculation with phosphate-solubilizing bacteria
Authors: Baudson Caroline , Delory Benjamin M. , Spaepen Stijn , du Jardin Patrick , Delaplace Pierre
Published: December 2019

Background

Mineral P fertilisers must be used wisely in order to preserve rock phosphate, a limited and non-renewable resource. The use of bio-inoculants to improve soil nutrient availability and trigger an efficient plant response to nutrient deficiency is one potential strategy in the attempt to decrease P inputs in agriculture.

Method

A gnotobiotic co-cultivation system was used to study the response ofBrachypodium distachyonto contrasted P supplies (soluble and poorly soluble forms of P) and inoculation with P solubilizing bacteria.Brachypodium’s responses to P conditions and inoculation with bacteria were studied in terms of developmental plasticity and P use efficiency.

Results

Brachypodiumshowed plasticity in its biomass allocation pattern in response to variable P conditions, specifically by prioritizing root development over shoot productivity under poorly soluble P conditions. Despite the ability of the bacteria to solubilize P, shoot productivity was depressed in plants inoculated with bacteria, although the root system development was maintained. The negative impact of bacteria on biomass production inBrachypodiummight be attributed to inadequate C supply to bacteria, an increased competition for P between both organisms under P-limiting conditions, or an accumulation of toxic bacterial metabolites in our cultivation system. Both P and inoculation treatments impacted root system morphology. The modulation ofBrachypodium’s developmental response to P supplies by P solubilizing bacteria did not lead to improved P use efficiency.

Conclusion

Our results support the hypothesis that plastic responses ofBrachypodiumcultivated under P-limited conditions are modulated by P solubilizing bacteria. The considered experimental context impacts plant–bacteria interactions. Choosing experimental conditions as close as possible to real ones is important in the selection of P solubilizing bacteria. Both persistent homology and allometric analyses proved to be useful tools that should be considered when studying the impact of bio-inoculants on plant development in response to varying nutritional context.
Construction of an inducible amyloid expression circuit in Bacillus megaterium: A case study with CsgA and TasA
Authors: Larsson Elin M. , McManus John B. , Murray Richard M.
Published: December 2019

Environmental applications of synthetic biology such as water remediation require engineered strains to function robustly in a fluctuating and potentially hostile environment. The construction of synthetic biofilm formation circuits could potentially alleviate this issue by promoting cell survival. Towards this end, we construct a xylose-inducible system for the expression of the functional amyloids CsgA and TasA in the soil bacterium Bacillus megaterium. We find that although both amyloids are expressed, only TasA is successfully exported from the cells. Furthermore, expression of CsgA results in a significant growth penalty for the cells while expression of TasA does not. Finally, we show that TasA expression conveys a small but detectable increase in cells’ adhesion to nickel beads. These results suggest that TasA is a promising candidate for future work on synthetic biofilm formation in B. megaterium.
Fast and Accurate Exhaustive Higher-Order Epistasis Search with BitEpi
Authors: Bayat Arash , Hosking Brendan , Jain Yatish , Hosking Cameron , Kodikara Milindi , Reti Daniel , Twine Natalie A. , Bauer Denis C.
Published: December 2019

Motivation

Complex genetic diseases may be modulated by a large number of epistatic interactions affecting a polygenic phenotype. Identifying these interactions is difficult due to computational complexity, especially in the case of higher-order interactions where more than two genomic variants are involved.

Results

In this paper, we present BitEpi, a fast and accurate method to test all possible combinations of up to four bi-allelic variants (i.e. Single Nucleotide Variant or SNV for short). BitEpi introduces a novel bitwise algorithm that is 2.1 and 56 times faster for 3-SNV and 4-SNV search, than established software. The novel entropy statistic used in BitEpi is 44% more accurate to identify interactive SNVs, incorporating a p-value-based significance testing. We demonstrate BitEpi on real world data of 4,900 samples and 87,000 SNPs. We also present EpiExplorer to visualize the potentially large number of individual and interacting SNVs in an interactive Cytoscape graph. EpiExplorer uses various visual elements to facilitate the discovery of true biological events in a complex polygenic environment.
The Structural Basis for Glycerol Permeation by human AQP7
Authors: Zhang Li , Yao Deqiang , Zhou Fu , Zhang Qing , Xia Ying , Wang Qian , Qin An , Zhao Jie , Li Dianfan , Zhou Lu , Cao Yu
Published: December 2019

Human glycerol channel AQP7 conducts glycerol release from adipocyte and entry into the cells in pancreatic islets, muscles and kidney tubule, and thus regulate glycerol metabolism in those tissues. Compared with other human aquaglyceroporins, AQP7 shows a less conserved “NPA” motif in the center cavity, and a pair of aromatic residues at Ar/R selectivity filter. To understand the structural basis for the glycerol conductance, we crystallized the human AQP7 and determined the structure at 3.7 Å. A substrate binding pocket was found near to the Ar/R filter and the bound glycerol molecule stabilized by R229. In vivo functional assay on human AQP7 as well as AQP3 and AQP10 demonstrated strong glycerol transportation activities at physiological condition. The human AQP7 structure reveals a fully closed conformation with its permeation pathway strictly confined by Ar/R filter at the exoplasmic side and the gate at the cytoplasmic side, and the dislocation of the residues at narrowest parts of glycerol pathway in AQP7 play a critical role in controlling the glycerol flux.
Age-related compensatory reconfiguration of PFC connections during episodic memory retrieval
Authors: Deng Lifu , Stanley Mathew L. , Monge Zachary A. , Wing Erik A. , Geib Benjamin R. , Davis Simon W. , Cabeza Roberto
Published: December 2019

During demanding cognitive tasks, older adults (OAs) frequently show greater prefrontal cortex (PFC) activity than younger adults (YAs). This age-related PFC activity increase is often associated with enhanced cognitive performance, suggesting functional compensation. However, the brain is a complex network of interconnected regions, and it is unclear how network connectivity of PFC regions differs for OAs vs. YAs. To investigate this, we examined the age-related difference in functional brain network mediating episodic memory retrieval. YAs and OAs participants encoded and then recalled visual scenes, and age-related differences in network topology during memory retrieval were investigated as a function of memory performance. We measured both quantitative changes in functional integration and qualitative reconfiguration in connectivity patterns. The study yielded three main findings. First, PFC regions were more functionally integrated with the rest of the brain network in OAs. Critically, this age-related increase in PFC integration was associated with better retrieval performance. Second, PFC regions showed stronger performance-related reconfiguration of connectivity patterns in OAs. Finally, the magnitude of PFC reconfiguration increases in OAs tracked reconfiguration reductions in the medial temporal lobe (MTL) – a core episodic memory region, suggesting that PFC connectivity in OAs may be compensating for MTL deficits.
Testing the effectiveness of principal components in adjusting for relatedness in genetic association studies
Authors: Yao Yiqi , Ochoa Alejandro
Published: December 2019

Modern genetic association studies require modeling population structure and family relatedness in order to calculate correct statistics. Principal Components Analysis (PCA) is one of the most common approaches for modeling this population structure, but nowadays the Linear Mixed-Effects Model (LMM) is believed by many to be a superior model. Remarkably, previous comparisons have been limited by testing PCA without varying the number of principal components (PCs), by simulating unrealistically simple population structures, and by not always measuring both type-I error control and predictive power. In this work, we thoroughly evaluate PCA with varying number of PCs alongside LMM in various realistic scenarios, including admixture together with family structure, measuring both null p-value uniformity and the area under the precision-recall curves. We find that PCA performs as well as LMM when enough PCs are used and the sample size is large, and find a remarkable robustness to extreme number of PCs. However, we notice decreased performance for PCA relative to LMM when sample sizes are small and when there is family structure, although LMM performance is highly variable. Altogether, our work suggests that PCA is a favorable approach for association studies when sample sizes are large and no close relatives exist in the data, and a hybrid approach of LMM with PCs may be the best of both worlds.
Predictive engineering and optimization of tryptophan metabolism in yeast through a combination of mechanistic and machine learning models
Authors: Zhang Jie , Petersen Søren D. , Radivojevic Tijana , Ramirez Andrés , Pérez Andrés , Abeliuk Eduardo , Sánchez Benjamín J. , Costello Zachary , Chen Yu , Fero Mike , Martin Hector Garcia , Nielsen Jens , Keasling Jay D. , Jensen Michael K.
Published: December 2019

In combination with advanced mechanistic modeling and the generation of high-quality multi-dimensional data sets, machine learning is becoming an integral part of understanding and engineering living systems. Here we show that mechanistic and machine learning models can complement each other and be used in a combined approach to enable accurate genotype-to-phenotype predictions. We use a genome-scale model to pinpoint engineering targets and produce a large combinatorial library of metabolic pathway designs with different promoters which, once phenotyped, provide the basis for machine learning algorithms to be trained and used for new design recommendations. The approach enables successful forward engineering of aromatic amino acid metabolism in yeast, with the new recommended designs improving tryptophan production by up to 17% compared to the best designs used for algorithm training, and ultimately producing a total increase of 106% in tryptophan accumulation compared to optimized reference designs. Based on a single high-throughput data-generation iteration, this study highlights the power of combining mechanistic and machine learning models to enhance their predictive power and effectively direct metabolic engineering efforts.
Metagenomic- and cultivation-based exploration of anaerobic chloroform biotransformation in hypersaline sediments as natural source of chloromethanes
Authors: Peng Peng , Lu Yue , Bosma Tom N.P. , Nijenhuis Ivonne , Nijsse Bart , Shetty Sudarshan A. , Ruecker Alexander , Umanetc Aleksandr , Ramiro-Garcia Javier , Kappler Andreas , Sipkema Detmer , Smidt Hauke , Atashgahi Siavash
Published: December 2019

Chloroform (CF) is an environmental contaminant that can be naturally formed in various environments ranging from forest soils to salt lakes. Here we investigated CF removal potential in sediments obtained from hypersaline lakes in Western Australia. Reductive dechlorination of CF to dichloromethane (DCM) was observed in enrichment cultures derived from sediments of Lake Strawbridge, which has been reported as a natural source of CF. The lack of CF removal in the abiotic control cultures without artificial electron donors indicated that the observed CF removal is a biotic process. Metabolite analysis with13C labelled CF in the sediment-free enrichment cultures (pH 8.5, salinity 5%) revealed that increasing the vitamin B12concentration from 0.04 to 4 μM enhanced CF removal, reduced DCM formation, and increased13CO2production, which is likely a product of CF oxidation. Known organohalide-respiring bacteria and reductive dehalogenase genes were neither detected by quantitative PCR nor metagenomic analysis. Rather, members of the orderClostridiales, known to co-metabolically transform CF to DCM and CO2, were detected in the enrichment cultures. Genome-resolved metagenome analysis indicated that their genomes encode enzymatic repertoires for the Wood-Ljungdahl pathway and cobalamin biosynthesis that are known to be involved in co-metabolic CF transformation.

Importance

More than 90% of the global CF emission to the atmosphere originates from natural sources, including saline environments such as salt lake sediments. However, knowledge about the microbial metabolism of CF in such extreme environments is lacking. Here we showed CF transformation potential in a hypersaline lake that was reported as a natural source of CF production. Application of interdisciplinary approaches of microbial cultivation, stable isotope labelling, and metagenomics aided in defining potential chloroform transformation pathways. This study indicates that microbiota may act as a filter to reduce CF emission from hypersaline lakes to the atmosphere, and expands our knowledge of halogen cycling in extreme hypersaline environments.
Parallel genomics uncover novel enterococcal-bacteriophage interactions
Authors: Chatterjee Anushila , Willett Julia L. E. , Nguyen Uyen Thy , Monogue Brendan , Palmer Kelli L. , Dunny Gary M. , Duerkop Breck A.
Published: December 2019

Bacteriophages (phages) have been proposed as alternative therapeutics for the treatment of multidrug resistant bacterial infections. However, there are major gaps in our understanding of the molecular events in bacterial cells that control how bacteria respond to phage predation. Using the model organismEnterococcus faecalis, we employed two distinct genomic approaches, transposon (Tn) library screening and RNA sequencing, to investigate the interaction ofE. faecaliswith a virulent phage. We discovered that a transcription factor encoding a LytR family response regulator controls the expression of enterococcal polysaccharide antigen (epa) genes that are involved in phage infection and bacterial fitness. In addition, we discovered that DNA mismatch repair mutants rapidly evolve phage adsorption deficiencies, underpinning a molecular basis forepamutation during phage infection. Transcriptomic profiling of phage infectedE. faecalisrevealed broad transcriptional changes influencing viral replication and progeny burst size. We also demonstrate that phage infection alters the expression of bacterial genes associated with intra and inter-bacterial interactions, including genes involved in quorum sensing and polymicrobial competition. Together our results suggest that phage predation has the potential to influence complex microbial behavior and may dictate how bacteria respond to external environmental stimuli. These responses could have collateral effects (positive or negative) on microbial communities such as the host microbiota during phage therapy.

Importance

We lack fundamental understanding of how phage infection influences bacterial gene expression and consequently how bacterial responses to phage infection affect the assembly of polymicrobial communities. Using parallel genomic approaches, we have discovered novel transcriptional regulators and metabolic genes that influence phage infection. The integration of whole genome transcriptomic profiling during phage infection has revealed the differential regulation of genes important for group behaviors and polymicrobial interactions. Our work suggests that therapeutic phages could more broadly influence bacterial community composition outside of their intended host targets.
Neural bases of phonological and semantic processing in early childhood
Authors: Mathur Avantika , Schultz Douglas , Wang Yingying
Published: December 2019

During the early period of reading development, children gain phonological (letter-to-sound mapping) and semantic knowledge (storage and retrieval of word meaning). Their reading ability changes rapidly, accompanied by their learning-induced brain plasticity as they learn to read. This study aims to identify the specialization of phonological and semantic processing in early childhood using a combination of univariate and multivariate pattern analysis. Nineteen typically developing children between the age of five to seven performed visual word-level phonological (rhyming) and semantic (related meaning) judgment tasks during functional magnetic resonance imaging (fMRI) scans. Our multivariate analysis showed that young children with good reading ability have already recruited the left hemispheric regions in the brain for phonological processing, including the inferior frontal gyrus (IFG), superior and middle temporal gyrus, and fusiform gyrus. Additionally, our multivariate results suggested that the sub-regions of the left IFG were specialized for different tasks. Our results suggest the left lateralization of fronto-temporal regions for phonological processing and bilateral activations of parietal regions for semantic processing during early childhood. Our findings indicate that the neural bases of reading have already begun to be shaped in early childhood for typically developing children, which can be used as a control baseline for comparison of children at-risk for reading difficulties.
Eco-evolutionary control of pathogens
Authors: Lässig Michael , Mustonen Ville
Published: December 2019

Control can alter the eco-evolutionary dynamics of a target pathogen in two ways, by changing its population size and by directed evolution of new functions. Here we develop a fitness model of eco-evolutionary control that specifies a minimum leverage for successful control against the intrinsic dynamics of the pathogen. We apply this model to pathogen control by molecular antibody-antigen binding with a tunable level of antibodies. By analytical solution, we obtain a phase diagram of optimal control and show that an error threshold separates regimes of successful and futile control. Our analysis identifies few, independently measurable fitness parameters that predict the outcome of control. We show that optimal control strategies depend on mutation rate and population size of the pathogen, and we discuss how monitoring and computational forecasting affect the efficiency of control. We argue that these results carry over to more general systems and are elements of an emerging eco-evolutionary control theory.