bluuebunny/crossref_metadata_2025 huggingface dataset:
Spurious regulatory connections dictate the expression-fitness landscape of translation termination factors
Authors: Lalanne Jean-Benoît , Parker Darren J. , Li Gene-Wei
Published: November 2020

During steady-state cell growth, individual enzymatic fluxes can be directly inferred from growth rate by mass conservation, but the inverse problem remains unsolved. Perturbing the flux and expression of a single enzyme could have pleiotropic effects that may or may not dominate the impact on cell fitness. Here we quantitatively dissect the molecular and global responses to varied expression of translation termination factors (peptide release factors, RFs) in bacterium Bacillus subtilis. While endogenous RF expression maximizes proliferation, deviations in expression lead to unexpected distal regulatory responses that dictate fitness reduction. Molecularly, RF depletion causes expression imbalance at specific operons, which activates master regulators and detrimentally overrides the transcriptome. Through these spurious connections, RF abundances are thus entrenched by focal points within the regulatory network, in one case located at a single stop codon. Such regulatory entrenchment suggests that predictive bottom-up models of expression-fitness landscapes will require near-exhaustive characterization of parts.

Highlights

Precision measurements enable multiscale expression-to-fitness mapping.

RF depletion leads to imbalanced translation for co-transcribed gene pairs.

Imbalanced translation induces unintended regulons to the detriment of cell fitness.

Swapping a single stop codon rewires global susceptibility to RF perturbation.
Trends of genetic changes uncovered by Env- and Eigen-GWAS in wheat and barley
Authors: Sharma Rajiv , Cockram James , Gardner Keith A. , Russell Joanne , Ramsay Luke , Thomas William TB , O’Sullivan Donal M. , Powell Wayne , Mackay Ian J.
Published: November 2020

The process of crop breeding over the last century has delivered new varieties with increased genetic gains, resulting in higher crop performance and yield. However in many cases, the underlying alleles and genomic regions that have underpinned this success remain unknown. This is due, in part, to the difficulty in generating sufficient phenotypic data on large numbers of historical varieties to allow such analyses to be undertaken. Here we demonstrate the ability to circumvent such bottlenecks by identifying genomic regions selected over 100 years of crop breeding using the age of a variety as a surrogate for yield. Using ‘environmental genome-wide association scans’ (EnvGWAS) on variety age in two of the world’s most important crops, wheat and barley, we found strong signals of selection across the genomes of our target crops. EnvGWAS identified 16 genomic regions in barley and 10 in wheat with contrasting patterns between spring and winter types of the two crops. To further examine changes in genome structure in wheat and barley over the past century, we used the same genotypic data to derive eigenvectors for deployment in EigenGWAS. This resulted in the detection of seven major chromosomal introgressions that contributed to adaptation in wheat. The deployment of both EigenGWAS and EnvGWAS based on variety age avoids costly phenotyping and will facilitate the identification of genomic tracts that have been under selection during plant breeding in underutilized historical cultivar collections. Our results not only demonstrate the potential of using historical cultivar collections coupled with genomic data to identify chromosomal regions that have been under selection but to also guide future plant breeding strategies to maximise the rate of genetic gain and adaptation in crop improvement programs.

Significance Statement

100 years of plant breeding have greatly improved crop adaptation, resilience, and productivity. Generating the trait data required for these studies is prohibitively expensive and can be impossible on large historical traits. This study reports using variety age and eigenvectors of the genomic relationship matrix as surrogate traits in GWAS to locate the genomic regions that have undergone selection during varietal development in wheat and barley. In several cases these were confirmed as associated with yield and other selected traits. The success and the simplicity of the approach means it can easily be extended to other crops with a recent recorded history of plant breeding and available genomic resources.
Characterisation and chemometric evaluation of 17 elements in ten seaweed species from Greenland
Authors: Kreissig Katharina Johanna , Hansen Lisbeth Truelstrup , Jensen Pernille Erland , Wegeberg Susse , Geertz-Hansen Ole , Sloth Jens J
Published: November 2020

Several Greenland seaweed species have potential as foods or food ingredients, both for local consumption and export. However, knowledge regarding their content of beneficial and deleterious elements on a species specific and geographical basis is lacking. This study investigated the content of 17 elements (As, Ca, Cd, Cr, Cu, Fe, Hg, I, K, Mg, Mn, Na, Ni, P, Pb, Se and Zn) in 77 samples of ten species (Agarum clathratum, Alaria esculenta, Ascophyllum nodosum, Fucus distichus, Fucus vesiculosus, Hedophyllum nigripes, Laminaria solidungula, Palmaria palmata, Saccharina latissima and Saccharina longicruris). Element profiles differed between species but showed similar patterns within the same family. For five species, different thallus parts were investigated separately, and showed different element profiles. A geographic origin comparison of Fucus species indicated regional differences. The seaweeds investigated were especially good sources of macrominerals (K > Na > Ca > Mg) and trace minerals, such as Fe. Iodine contents were high, especially in macroalgae of the family Laminariaceae. None of the samples exceeded the EU maximum levels for Cd, Hg or Pb, but some exceeded the stricter French regulations, especially for Cd and I. In conclusion, these ten species are promising food items.
Spatial Suitability Modeling of Zoonosis: Implicated Risk Areas of B. anthracis and Trends under climate change Scenarios in Ethiopia
Authors: Yousuf Michael A , Asfaw Solomon , Mengistu Shimelis , Husen Mohammedsham
Published: November 2020

The causative agent of Anthrax B. anthracis has long been known to cause disease in animals and humans. Its worldwide distribution includes Ethiopia as an endemic country to the disease. The current study was aimed at identifying and developing risk maps, in areas that are suitable for the persistence of anthrax spores under climate change scenarios by using anthrax occurrence data and other predictor variables in MaxEnt model. A total of 158 occurrence locations were used as inputs along 10 current bioclimatic, future climatic grids and topographic covariates to develop a model and evaluate the individual contribution of each variable to the presence of B. anthracis in Ethiopia. It’s concluded that the most important variables limiting the distribution of B. anthracis in Ethiopia were Temperature, Precipitation, and Elevation. Under HADGEM2-ES future modeling scenarios except for RCP 8.5/2050 there is a decrease in areas of suitability from Current scenario under RCP 2.6/2050, RCP 2.6/2070, and RCP 8.5/2070. Subtle expansions of suitable areas are identified under RCP 2.6/2050 and RCP 2.6/2070 in the eastern parts of Ethiopia. However, there are small portions of southern areas that are expected to lose suitable habitats under all future scenarios. These findings could help health management authorities to formulate prevention and control strategies of anthrax in suitable areas under B. anthracis.
Biosynthesis of dihydroquercetin inEscherichia colifrom glycerol
Authors: Park Seon Young , Yang Dongsoo , Ha Shin Hee , Lee Sang Yup
Published: November 2020

Phenylpropanoids are a group of diverse natural products derived from aromatic amino acids. Although their demands are high both as drugs and nutraceuticals, their production mainly depends on inefficient extraction from plants. To achieve sustainable production of phenylpropanoids, engineering model microorganisms suchas Escherichia colihas been sought, but most strains require supplementation of expensive precursors. Here, we report one-step production of a representative phenylpropanoid, dihydroquercetin (DHQ), from simple carbon sources inE. colifor the first time. The best DHQ producer strain capable of producing 239.4 mg/L of DHQ from glycerol was obtained by optimizing the biosynthetic pathway and engineering the signal peptide of cytochrome P450 (TT7) fromArabidopsis thaliana. The engineered plant P450 could produce a significantly higher titer of DHQ than a bacterial monooxygenase, showing the potential of employing plant P450s for the production of diverse natural products that has been previously difficult in bacterial hosts. This study will serve as a guideline for industrial production of pharmaceutically important yet complex natural products.
Fast and sensitive taxonomic assignment to metagenomic contigs
Authors: Mirdita M. , Steinegger M. , Breitwieser F. , Söding J. , Levy Karin E.
Published: November 2020

MMseqs2 taxonomy is a new tool to assign taxonomic labels to metagenomic contigs. It extracts all possible protein fragments from each contig, quickly retains those that can contribute to taxonomic annotation, assigns them with robust labels and determines the contig’s taxonomic identity by weighted voting. Its fragment extraction step is suitable for the analysis of all domains of life. MMseqs2 taxonomy is 2-18x faster than state-of-the-art tools and also contains new modules for creating and manipulating taxonomic reference databases as well as reporting and visualizing taxonomic assignments.

Availability

MMseqs2 taxonomy is part of the MMseqs2 free open-source software package available for Linux, macOS and Windows at https://mmseqs.com.

Contact

eli.levy.karin@gmail.com
Distinct role of nucleus accumbens D2-MSN projections to ventral pallidum in different phases of motivated behavior
Authors: Soares-Cunha Carina , Correia Raquel , Domingues Ana Verónica , Coimbra Bárbara , de Vasconcelos Nivaldo AP , Pinto Luísa , Sousa Nuno , Rodrigues Ana João
Published: November 2020

The nucleus accumbens (NAc) is a key region in motivated behaviors. NAc medium spiny neurons (MSNs) are divided into those expressing dopamine receptor D1 or D2. Classically, D1- and D2-MSNs have been described as having opposing roles in reinforcement but recent evidence suggests a more complex role for D2-MSNs.

Here we show that optogenetic modulation of D2-MSN to ventral pallidum (VP) projections during different stages of motivated behavior has contrasting effects in motivation. Activation of D2-MSN-VP projections during a reward-predicting cue results in increased motivational drive, whereas activation at reward delivery results in decreased motivation; optical inhibition has the opposite behavioral effect. In addition, in a free choice instrumental task, animals prefer the lever that originates one pellet in opposition to pellet plus D2-MSN-VP optogenetic activation, and vice versa for optogenetic inhibition.

In summary, D2-MSN-VP projections play different (and even opposing) roles in distinct phases of motivated behavior.
ninaDregulates cholesterol homeostasis from the midgut which protects against neurodegeneration
Authors: Soulé Stéphanie , Martin Jean-René
Published: November 2020

Cholesterol is crucial to maintain normal cellular function. In human, it has also been involved in various neurodegeneration processes, as Niemann-Pick and Alzheimer diseases. Recently, we have identified a small nucleolar RNA (jouvence) required in the epithelial cells of the gut (enterocytes), and showed that its overexpression extends lifespan. A transcriptomic analysis has revealed a deregulation of several genes injouvencemutants. Among them,ninaDencoding a mammalian homolog to class B Scavenger receptor is importantly upregulated. InDrosophila, ninaDis required for the uptake of the dietary carotenoid, used for the formation of rhodopsin. Here, we show thatjouvence-deleted flies are deficient in cholesterol-ester, as well as old flies present neurodegenerative lesions. RestoringninaDmRNA expression level in enterocytes restores the metabolic cholesterol-ester level, prevents neurodegeneration and extends lifespan, revealing a gut-brain axis. Our studies demonstrates thatninaDis a central regulator of cholesterol homeostasis and a longevity-promoting factor.
The Dutch Microbiome Project defines factors that shape the healthy gut microbiome
Authors: Gacesa R. , Kurilshikov A. , Vich Vila A. , Sinha T. , Klaassen M.A.Y. , Bolte L.A. , Andreu-Sánchez S. , Chen L. , Collij V. , Hu S. , Dekens J.A.M. , Lenters V.C. , Björk J.R. , Swarte J.C. , Swertz M.A. , Jansen B.H. , Gelderloos-Arends J. ,   Lifelines cohort study, Hofker M. , Vermeulen R.C.H. , Sanna S. , Harmsen H.J.M. , Wijmenga C. , Fu J. , Zhernakova A. , Weersma R.K.
Published: November 2020

The gut microbiome is associated with diverse diseases, but the universal signature of an (un)healthy microbiome remains elusive and there is a need to understand how genetics, exposome, lifestyle and diet shape the microbiome in health and disease. To fill this gap, we profiled bacterial composition, function, antibiotic resistance and virulence factors in the gut microbiomes of 8,208 Dutch individuals from a three-generational cohort comprising 2,756 families. We then correlated this to 241 host and environmental factors, including physical and mental health, medication use, diet, socioeconomic factors and childhood and current exposome. We identify that the microbiome is primarily shaped by environment and cohousing. Only ∼13% of taxa are heritable, which are enriched with highly prevalent and health-associated bacteria. By identifying 2,856 associations between microbiome and health, we find that seemingly unrelated diseases share a common signature that is independent of comorbidities. Furthermore, we identify 7,519 associations between microbiome features and diet, socioeconomics and early life and current exposome, of which numerous early-life and current factors are particularly linked to the microbiome. Overall, this study provides a comprehensive overview of gut microbiome and the underlying impact of heritability and exposures that will facilitate future development of microbiome-targeted therapies.
A spiking neural circuit model for learning multi-sensory integration
Authors: Song Deying , Niu Xueyan , Zhang Wen-Hao , Lee Tai Sing
Published: November 2020

Neurons in visual and vestibular information integration areas of macaque brain such as medial superior temporal (MSTd) and ventral intraparietal (VIP) have been classified into congruent neurons and opposite neurons, which prefer congruent inputs and opposite inputs from the two sensory modalities, respectively. In this work, we propose a mechanistic spiking neural model that can account for the emergence of congruent and opposite neurons and their interactions in a neural circuit for multi-sensory integration. The spiking neural circuit model is adopted from an established model for the circuits of the primary visual cortex with little changes in parameters. The network can learn, based on the basic Hebbian learning principle, the correct topological organization and behaviors of the congruent and opposite neurons that have been proposed to play a role in multi-sensory integration. This work explore the constraints and the conditions that lead to the development of a proposed neural circuit for cue integration. It also demonstrates that such neural circuit might indeed be a canonical circuit shared by computations in many cortical areas.
Positive effects of crop diversity on productivity driven by changes in soil microbial composition
Authors: Stefan Laura , Hartmann Martin , Engbersen Nadine , Six Johan , Schöb Christian
Published: November 2020

Intensive agriculture has major negative impacts on ecosystem diversity and functioning, including that of soils. The associated reduction of soil biodiversity and essential soil functions, such as nutrient cycling, can restrict plant growth and crop yield. By increasing plant diversity in agricultural systems, intercropping could be a promising way to foster soil microbial diversity and functioning. However, plant–microbe interactions and the extent to which they influence crop yield under field conditions are still poorly understood. In this study, we performed an extensive intercropping experiment using eight crop species and 40 different crop mixtures to investigate how crop diversity affects soil microbial diversity and functions, and whether these changes subsequently affect crop yield. Experiments were carried out in mesocosms under natural conditions in Switzerland and in Spain, two countries with drastically different soils and climate, and our crop communities included either one, two or four species. We sampled and sequenced soil microbial DNA to assess soil microbial diversity, and measured soil basal respiration as a proxy for soil activity. Results indicate that in Switzerland, increasing crop diversity led to shifts in soil microbial community composition, and in particular to an increase of several plant-growth promoting microbes, such as members of the bacterial phylum Actinobacteria. These shifts in community composition subsequently led to a 15 and 35% increase in crop yield in 2 and 4-species mixtures, respectively. This suggests that the positive effects of crop diversity on crop productivity can partially be explained by changes in soil microbial composition. However, the effects of crop diversity on soil microbes were relatively small compared to the effects of abiotic factors such as fertilization (3 times larger) or soil moisture (3 times larger). Furthermore, these processes were context-dependent: in Spain, where soil resources were limited, soil microbial communities did not respond to crop diversity, and their effect on crop yield was less strong. This research highlights the potential beneficial role of soil microbial communities in intercropping systems, while also reflecting on the relative importance of crop diversity compared to abiotic drivers of microbiomes, thereby emphasizing the context-dependence of crop–microbe relationships.
Sleeping ribosomes: bacterial signaling triggers RaiA mediated persistence to aminoglycosides
Authors: Lang Manon , Krin Evelyne , Korlowski Chloé , Sismeiro Odile , Varet Hugo , Coppée Jean-Yves , Mazel Didier , Baharoglu Zeynep
Published: November 2020

Indole is a small molecule derived from tryptophan degradation and proposed to be involved in bacterial signaling. We find that indole secretion is induced by sublethal tobramycin concentrations and increases persistence to aminoglycosides in V. cholerae. Indole transcriptomics showed strongly increased expression of raiA, a ribosome associated factor. Deletion of raiA abolishes the appearance of indole dependent persisters to aminoglycosides, while its overexpression leads to 100-fold increase of persisters, and a reduction in lag phase, evocative of increased active 70S ribosome content, which was confirmed by sucrose gradient analysis. We propose that, under stress conditions, inactive 70S ribosomes are associated with RaiA to be stored and rapidly reactivated when growth conditions become favorable again, in a mechanism different than ribosome hibernation. Our results point to an active process of persistent cell formation, through ribosome protection during translational stress and relief upon antibiotic removal. Translation is a universal process, and these results could help elucidate a mechanism of persistence formation in a controlled, thus inducible way.
Overexpressed microrna-129-5p reverses CCl4-Induced hepatic fibrosis by suppressing PEG3 expression and the NF-κB signaling pathway
Authors: Sun Shengtao , Ma Yunxia , Li Yinfeng
Published: November 2020

The authors have withdrawn their manuscript whilst they perform additional experiments to test some of their conclusions further. This preprint does not represent the final version. Therefore, the authors do not wish this work to be cited as reference for the project.
Unveiling functions of the visual cortex using task-specific deep neural networks
Authors: Dwivedi Kshitij , Bonner Michael F. , Cichy Radoslaw Martin , Roig Gemma
Published: November 2020

The human visual cortex enables visual perception through a cascade of hierarchical computations in cortical regions with distinct functionalities. Here, we introduce an AI-driven approach to discover the functional mapping of the visual cortex. We related human brain responses to scene images measured with functional MRI (fMRI) systematically to a diverse set of deep neural networks (DNNs) optimized to perform different scene perception tasks. We found a structured mapping between DNN tasks and brain regions along the ventral and dorsal visual streams. Low-level visual tasks mapped onto early brain regions, 3-dimensional scene perception tasks mapped onto the dorsal stream, and semantic tasks mapped onto the ventral stream. This mapping was of high fidelity, with more than 60% of the explainable variance in nine key regions being explained. Together, our results provide a novel functional mapping of the human visual cortex and demonstrate the power of the computational approach.
A one-shot learning signal in monkey prefrontal cortex
Authors: Achterberg Jascha , Kadohisa Mikiko , Watanabe Kei , Kusunoki Makoto , Buckley Mark J , Duncan John
Published: November 2020

Much animal learning is slow, with cumulative changes in behavior driven by reward prediction errors. When the abstract structure of a problem is known, however, both animals and formal learning models can rapidly attach new items to their roles within this structure, sometimes in a single trial. Frontal cortex is likely to play a key role in this process. To examine information seeking and use in a known problem structure, we trained monkeys in a novel explore/exploit task, requiring the animal first to test objects for their association with reward, then, once rewarded objects were found, to re-select them on further trials for further rewards. Many cells in the frontal cortex showed an explore/exploit preference, changing activity in a signal trial to align with one-shot learning in the monkeys’ behaviour. In contrast to this binary switch, these cells showed little evidence of continuous changes linked to expectancy or prediction error. Explore/exploit preferences were independent for two stages of the trial, object selection and receipt of feedback. Within an established task structure, frontal activity may control the separate operations of explore and exploit, switching in one trial between the two.

Significance statement

Much animal learning is slow, with cumulative changes in behavior driven by reward prediction errors. When the abstract structure a problem is known, however, both animals and formal learning models can rapidly attach new items to their roles within this structure. To address transitions in neural activity during one-shot learning, we trained monkeys in an explore/exploit task using familiar objects and a highly familiar task structure. In contrast to continuous changes reflecting expectancy or prediction error, frontal neurons showed a binary, one-shot switch between explore and exploit. Within an established task structure, frontal activity may control the separate operations of exploring alternative objects to establish their current role, then exploiting this knowledge for further reward.
Manufacturing Stable Bacteriophage Powders Using Thin Film Freeze-drying Technology
Authors: Zhang Yajie , Soto Melissa , Ghosh Debadyuti , Williams Robert O.
Published: November 2020

Recently, therapeutic uses of bacteriophage (phage) are gaining increased attention, yet common liquid phage formulations require cold chain storage that limits their potential use. Phage therapy is considered as an alternative to antibiotics for bacterial infections and more significantly a promising solution for the ever-increasing prevalence of multi-drug resistance (MDR) pathogens. One of the most promising applications of this therapy is to treat pulmonary bacterial infections. To efficiently deliver therapeutic phage to the lungs, phage formulations that allow for nebulization or dry powder inhalation are under active development. Several conventional particle engineering technologies have been applied in the development of dry powder inhalers (DPI), including spray drying, spray freeze drying, and atmospheric spray freeze drying, but these processes have their own disadvantages that limit their use with bacteriophage formulations and delivery. In our work, we hypothesize that thin film freeze-drying (TFFD) can be used to produce brittle matrix powders containing phage that may be suitable for delivery by several routes of administration, including by nebulization after reconstitution and by intranasal or inhalation delivery of the resulting dry powder. Here we selected T7 bacteriophage as our model phage in a preliminary screening study and found that a binary excipient matrix of sucrose and leucine at ratios of 80:20 or 75:25 by weight, protected bacteriophage from the stresses encountered during the TFFD process. In addition, we confirm that incorporating a buffer system during the TFFD process significantly improved the survival of phage during the ultra-rapid freezing step of the TFFD process and subsequent sublimation step in the lyophilization process. This preservation of phage bioactivity was significantly better than that observed for formulations without a buffer system. The titer loss of phage in standard SM buffer (Tris/NaCl/MgSO4/gelatin) containing formulation was as low as 0.2 log plaque forming units (pfu), which indicates that phage functionality was preserved after the TFFD process. Moreover, the presence of buffers markedly reduced the geometric particle sizes as determined by a dry dispersion method using laser diffraction, which indicates that the TFFD phage powder formulations were easily sheared into smaller powder aggregates, an ideal property for facilitating pulmonary delivery through DPIs. From these findings, we show that TFFD is a particle engineering method that can successfully produce phage containing powders that possess the desired properties for bioactivity and inhalation therapy.
Divergent pallidal pathways underlying distinct Parkinsonian behavioral deficits
Authors: Lilascharoen Varoth , Wang Eric Hou-Jen , Do Nam , Pate Stefan Carl , Tran Amanda Ngoc , Wang Xiao-Yun , Park Young-Gyun , Chung Kwanghun , Lim Byung Kook
Published: November 2020

The basal ganglia are a group of subcortical nuclei that regulates motor and cognitive functions1,2. Recent identification of neuronal heterogeneity in the basal ganglia suggests that functionally distinct neural circuits defined by their efferent projections exist even within the same nuclei3-5. This distinction may account for a multitude of symptoms associated with basal ganglia disorders such as Parkinson’s disease (PD)6,7. However, our incomplete understanding of the basal ganglia functional organization has hindered further investigation of individual circuits that may underlie different behavioral symptoms in disease states. Here we functionally define two distinct classes of parvalbumin-expressing neurons in the mouse external globus pallidus (GPe-PV) embedded within discrete neural pathways and establish their contributions to different Parkinsonian behavioral deficits. We find that GPe-PV neurons projecting to the substantia nigra pars reticulata (SNr) or parafascicular thalamus (PF) undergo different electrophysiological adaptations in response to dopamine depletion. Furthermore, counteracting these adaptations in each population can selectively alleviate movement deficits or behavioral inflexibility in a Parkinsonian mouse model. Our findings provide a novel framework to understand the circuit basis of separate behavioral symptoms in Parkinsonian state which could provide better strategies for the treatment of PD.
3D DNA structural barcode copying and random access
Authors: Bošković Filip , Ohmann Alexander , Keyser Ulrich F. , Chen Kaikai
Published: November 2020

Three-dimensional (3D) DNA nanostructures built via DNA self-assembly have established recent applications in multiplexed biosensing and storing digital information. However, a key challenge is that 3D DNA structures are not easily copied which is of vital importance for their large-scale production and for access to desired molecules by target-specific amplification. Here, we build 3D DNA structural barcodes and demonstrate the copying and random access of the barcodes from a library of molecules using a modified polymerase chain reaction (PCR). The 3D barcodes were assembled by annealing a single-stranded DNA scaffold with complementary short oligonucleotides containing 3D protrusions at defined locations. DNA nicks in these structures are ligated to facilitate barcode copying using PCR. To randomly access a target from a library of barcodes, we employ a non-complementary end in the DNA construct that serves as a barcode-specific primer template. Readout of the 3D DNA structural barcodes was performed with nanopore measurements. Our study provides a roadmap for convenient production of large quantities of self-assembled 3D DNA nanostructures. In addition, this strategy offers access to specific targets, a crucial capability for multiplexed single-molecule sensing and for DNA data storage.
Viscoelasticity of biomolecular condensates conforms to the Jeffreys model
Authors: Zhou Huan-Xiang
Published: November 2020

Biomolecular condensates, largely by virtue of their material properties, are revolutionizing biology, and yet physical understanding of these properties is lagging. Here I show that the viscoelasticity of condensates can be captured by a simple model, comprising a component where shear relaxation is an exponential function of time and a component that is purely viscous (corresponding to instantaneous shear relaxation). Modulation of intermolecular interactions, e.g., by adding salt, can disparately affect the two components, such that the exponentially-relaxing component may dominate at low salt whereas the purely viscous component may dominate at high salt. Condensates have a tendency to fuse, with the dynamics accelerated by surface tension and impeded by viscosity. For fast-fusion condensates, shear relaxation may become rate-limiting. These insights help narrow the gap in understanding between the biology and physics of biomolecular condensates.
Whole-brain dynamics of human sensorimotor adaptation
Authors: Standage Dominic I. , Areshenkoff Corson N. , Gale Daniel J. , Nashed Joseph Y. , Flanagan J. Randall , Gallivan Jason P.
Published: November 2020

Humans vary greatly in their motor learning abilities, yet little is known about the neural processes that underlie this variability. We identified distinct profiles of human sensorimotor adaptation that emerged across two days of learning, linking these profiles to the dynamics of whole-brain functional networks early on the first day, when cognitive strategies toward sensorimotor adaptation are believed to be most prominent. During early learning, greater recruitment of a network of higher-order brain regions, involving prefrontal and anterior temporal cortex, was associated with faster learning. At the same time, greater integration of this ‘cognitive network’ with a sensorimotor network was associated with slower learning, consistent with the notion that cognitive strategies toward adaptation operate in parallel with implicit learning processes of the sensorimotor system. On the second day, greater recruitment of a network that included the hippocampus was associated with faster re-learning, consistent with the notion that savings involves declarative memory systems. Together, these findings provide novel evidence for the role of higher-order brain systems in driving individual differences in adaptation.
Mfd affects global transcription and the physiology of stressed Bacillus subtilis cells
Authors: Martin Holly Anne , Sundararajan Anitha , Ermi Tatiana , Heron Robert , Gonzales Jason , Lee Kaiden , Anguiano-Mendez Diana , Schilkey Faye , Pedraza-Reyes Mario , Robleto Eduardo A.
Published: November 2020

For several decades, Mfd has been studied as the bacterial transcription-coupled repair factor. However, recent observations indicate that this factor influences cell functions beyond DNA repair. Our lab recently described a role for Mfd in disulfide stress that was independent of its function in nucleotide excision repair and base excision repair. Because reports showed that Mfd influenced transcription of single genes, we investigated the global differences in transcription in wild-type and mfd mutant growth-limited cells in the presence and absence of diamide. Surprisingly, we found 1,997 genes differentially expressed in Mfd- cells in the absence of diamide. Using gene knockouts, we investigated the effect of genetic interactions between Mfd and the genes in its regulon on the response to disulfide stress. Interestingly, we found that Mfd interactions were complex and identified additive, epistatic, and suppressor effects in the response to disulfide stress. Pathway enrichment analysis of our RNASeq assay indicated that major biological functions, including translation, endospore formation, pyrimidine metabolism, and motility, were affected by the loss of Mfd. Further, our RNASeq findings correlated with phenotypic changes in growth in minimal media, motility, and sensitivity to antibiotics that target the cell envelope, transcription, and DNA replication. Our results suggest that Mfd has profound effects on the modulation of the transcriptome and on bacterial physiology, particularly in cells experiencing nutritional and oxidative stress.
Dynamic decision policy reconfiguration under outcome uncertainty
Authors: Bond Krista , Dunovan Kyle , Porter Alexis , Rubin Jonathan , Verstynen Timothy
Published: November 2020

In uncertain or unstable environments, sometimes the best decision is to change your mind. To shed light on this flexibility, we evaluated how the underlying decision policy adapts when the most rewarding action changes. Human participants performed a dynamic two-armed bandit task that manipulated the certainty in relative reward (conflict) and the reliability of action-outcomes (volatility). Continuous estimates of conflict and volatility contributed to shifts in exploratory states by changing both the rate of evidence accumulation (drift rate) and the amount of evidence needed to make a decision (boundary height), respectively. At the trialwise level, following a switch in the optimal choice, the drift rate plummets and the boundary height weakly spikes, leading to a slow exploratory state. We find that the drift rate drives most of this response, with an unreliable contribution of boundary height across experiments. Surprisingly, we find no evidence that pupillary responses associated with decision policy changes. We conclude that humans show a stereotypical shift in their decision policies in response to environmental changes.
Diverse molecular mechanisms contribute to differential expression of human duplicated genes
Authors: Shew Colin J. , Carmona-Mora Paulina , Soto Daniela C. , Mastoras Mira , Roberts Elizabeth , Rosas Joseph , Jagannathan Dhriti , Kaya Gulhan , O’Geene Henriette , Dennis Megan Y.
Published: November 2020

Emerging evidence links genes within human-specific segmental duplications (HSDs) to traits and diseases unique to our species. Strikingly, despite being nearly identical by sequence (>98.5%), paralogous HSD genes are differentially expressed across human cell and tissue types, though the underlying mechanisms have not been examined. We compared cross-tissue mRNA levels of 75 HSD genes from 30 families between humans and chimpanzees and found expression patterns consistent with pseudo- or neofunctionalization. In general, ancestral paralogs exhibited greatest expression conservation with chimpanzee orthologs, though exceptions suggest certain derived paralogs may retain or supplant ancestral functions. Concordantly, analysis of long-read isoform sequencing datasets from diverse human tissues and cell lines found that about half of derived paralogs exhibited globally lower expression. To understand mechanisms underlying these differences, we leveraged data from human lymphoblastoid cell lines (LCLs) and found no relationship between paralogous expression divergence and post- transcriptional regulation, sequence divergence, or copy number variation. Considering cis-regulation, we reanalyzed ENCODE data and recovered hundreds of previously unidentified candidate CREs in HSDs. We also generated large-insert ChIP-sequencing data for active chromatin features in an LCL to better distinguish paralogous regions. Some duplicated CREs were sufficient to drive differential reporter activity, suggesting they may contribute to divergent cis-regulation of paralogous genes. This work provides evidence that cis-regulatory divergence contributes to novel expression patterns of recent gene duplicates in humans.
Molecular imaging reveals a high degree of cross-seeding of spontaneous metastases in a novel mouse model of synchronous bilateral breast cancer
Authors: Liu Shirley , Nyström Nivin N , Kelly John J , Hamilton Amanda M , Fu Yanghao , Ronald John A
Published: November 2020

Synchronous bilateral breast cancer (SBBC) patients present with cancer in both breasts at the time of diagnosis or within a short time interval. They show higher rates of metastasis and lower overall survival compared to women with unilateral breast cancer. However, the lack of a preclinical model has led to a dearth in knowledge regarding the patterns of SBBC metastasis. Here we established an SBBC model and used molecular imaging to visualize the development of spontaneous lung metastases arising from each primary tumor. We engineered human breast cancer cells to express either Akaluc or Antares2 for bioluminescence imaging (BLI), and tdTomato or zsGreen for ex vivo fluorescence microscopy. Both cell populations were implanted into contralateral mammary fat pads of mice (n=10) and BLI was performed weekly for up to day 29 (n=3), 38 (n=4), or 42 (n=3). Signal from both Antares2 and Akaluc was first detected in the lungs on day 28 and was present in 9 of 10 mice at endpoint. Ex vivo fluorescence microscopy of the lungs revealed that for mice sacrificed on day 38, a significant percentage of micrometastases were composed of cancer cells from both primary tumors (mean 37%; range 27% to 45%), while two mice sacrificed on day 42 showed percentages of 51% and 70%. These results reveal a high degree of metastatic cross-seeding which may contribute to faster metastatic growth and intratumoral heterogeneity. We posit our work will help understand treatment resistance and optimal planning of treatment for SBBC patients.
Comparative analysis of early divergent land plants and construction of DNA tools for hyper-expression in Marchantia chloroplasts
Authors: Frangedakis Eftychios , Guzman-Chavez Fernando , Rebmann Marius , Markel Kasey , Yu Ying , Perraki Artemis , Tse Sze Wai , Liu Yang , Rever Jenna , Sauret-Gueto Susanna , Goffinet Bernard , Schneider Harald , Haseloff Jim
Published: November 2020

Chloroplast genes are present at high ploidy in plants, and capable of driving very high levels of gene expression if mRNA production and stability are properly regulated. Marchantia polymorpha is a simple model plant that allows rapid transformation studies, however post-transcriptional regulation in plastids is poorly characterized in this liverwort. We have mapped patterns of transcription in Marchantia chloroplasts. Furthermore, we have obtained and compared sequences from 51 early-divergent plant species, and identified putative sites for pentatricopeptide repeat protein binding that are thought to play important roles in mRNA stabilisation. Candidate binding sites were tested for their ability to confer high levels of reporter gene expression in Marchantia chloroplasts, and levels of protein production and effects on growth were measured in homoplasmic transformed plants. We have produced novel DNA tools for protein hyper-expression in a facile plant system that is a test-bed for chloroplast engineering.
On testing structural identifiability by a simple scaling method: relying on scaling symmetries can be misleading
Authors: Villaverde Alejandro F. , Feixas Gemma Massonis
Published: December 2020

A recent paper (Castro M, de Boer RJ, “Testing structural identifiability by a simple scaling method”, PLOS Computational Biology, 2020, 16(11):e1008248) introduces the Scaling Invariance Method (SIM) for analysing structural local identifiability and observability. These two properties define mathematically the possibility of determining the values of the parameters (identifiability) and states (observability) of a dynamic model by observing its output. In this note we warn that SIM considers scaling symmetries as the only possible cause of non-identifiability and non-observability. We show that other types of symmetries can cause the same problems without being detected by SIM, and that in those cases the method may yield a wrong result. Finally, we demonstrate how to analyse structural local identifiability and observability with symbolic computation tools that do not exhibit those issues.
Evidence for both phylogenetic conservatism and lability in the evolution of secondary chemistry in a tropical angiosperm radiation
Authors: Uckele Kathryn A. , Jahner Joshua P. , Tepe Eric J. , Richards Lora A. , Dyer Lee A. , Ochsenrider Kaitlin M. , Philbin Casey S. , Kato Massuo J. , Yamaguchi Lydia F. , Forister Matthew L. , Smilanich Angela M. , Dodson Craig D. , Jeffrey Christopher S. , Parchman Thomas L.
Published: December 2020

Over evolutionary timescales, shifts in plant secondary chemistry may be associated with patterns of diversification in associated arthropods. Although foundational hypotheses of plant-insect codiversification and plant defense theory posit closely related plants should have similar chemical profiles, numerous studies have documented variation in the degree of phylogenetic signal, suggesting phytochemical evolution is more nuanced than initially assumed. We utilize proton nuclear magnetic resonance (1H NMR) data, chemical classification, and genotyping-by-sequencing to resolve evolutionary relationships and characterize the evolution of secondary chemistry in the Neotropical plant clade Radula (Piper; Piperaceae). Sequencing data substantially improved phylogenetic resolution relative to past studies, and spectroscopic characterization revealed the presence of 35 metabolite classes. Broad metabolite classes displayed strong phylogenetic signal, whereas the crude1H NMR spectra featured evolutionary lability in chemical resonances. Evolutionary correlations were detected in two pairs of compound classes (flavonoids with chalcones;p-alkenyl phenols with kavalactones), where the gain or loss of a class was dependent on the other’s state. Overall, the evolution of secondary chemistry in Radula is characterized by strong phylogenetic signal of broad compound classes and concomitant evolutionary lability of specialized chemical motifs, consistent with both classic evolutionary hypotheses and recent examinations of phytochemical evolution in young lineages.
Noise-induced properties of active dendrites
Authors: van Vreeswijk Carl , Farkhooi Farzada
Published: December 2020

Dendrites play an essential role in the integration of highly fluctuating input into neurons across all nervous systems. Nevertheless, they are often studied under the conditions where inputs to dendrites are sparse. Up to date, the dynamic properties of active dendrites facing in-vivo-like fluctuating input remains elusive. In this paper, we uncover fundamentally new dynamics in a canonical model of a dendritic compartment with active calcium channels, receiving in-vivo-like fluctuating input. We show in-vivo-like noise induces non-monotonic or bistable dynamics in the input-output relation of a dendritic compartment, both of which are absent in a noiseless condition. Our analysis shows that the timescales of the activation gating variable of the dendritic calcium dynamics determine noise-induced spontaneous order in the system. Noise can induce non-monotonicity or bistability with fast or slow calcium activation respectively. We characterize these noise-induced phenomena and their influence on the input-output relation. Furthermore, we show that timescales of the emerging stochastic bistable dynamics go far beyond a deterministic system due to stochastic switching between the solutions. Our results reveal that noise contributes to sustained dendritic nonlinearities, and it could be considered a principal component of the dendritic input integration strategies.
Assembly of the amphibian microbiome is influenced by the effects of land-use change on environmental reservoirs
Authors: Barnes Elle M. , Kutos Steve , Naghshineh Nina , Mesko Marissa , You Qing , Lewis J.D.
Published: December 2020

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A growing focus in microbial ecology is understanding of how beneficial microbiome function is created and maintained through both stochastic and deterministic assembly mechanisms. This study explores the role of both the environment and disease in regulating the composition of microbial species pools in the soil and local communities of an amphibian host. To address this, we compared the microbiomes of over 200Plethodon cinereussalamanders along a 65km land-use gradient in the greater New York metropolitan area and paired these with associated soil cores. Additionally, we characterized the diversity of bacterial and fungal symbionts that putatively inhibit the pathogenic fungusBatrachochytrium dendrobatidis. We predicted that if soil functions as the main regional species pool to amphibian skin, variation in skin microbial community composition would correlate with changes seen in soil. We found that salamanders share many microbial taxa with their soil environment but that these two microbiomes exhibit key differences, especially in the relative abundances of the bacteria phyla Acidobacteria, Actinobacteria, and Proteobacteria and the fungal phyla Ascomycota and genusBasidiobolus. Microbial community composition varied with changes in land-use associated factors such as canopy cover, impervious surface, and concentrations of the soil elements Al, Ni, and Hg, creating site-specific compositions. In addition, high dissimilarity among individual amphibian microbiomes across and within sites suggest that both stochastic and deterministic mechanisms guide assembly of microbes onto amphibian skin, with likely consequences in disease preventative function.
Large Neutral Amino acid uptake and mTOR activation within CD4+ T cells coordinate Type 2 immunity and host resistance toTrichuris muris
Authors: Krauss Maria Z , Hayes Kelly S , Villegas-Mendez Ana , Hepworth Matthew R , Sinclair Linda V , Couper Kevin N , Grencis Richard K
Published: December 2020

Trichuris trichiura(whipworm) is a gastrointestinal nematode that infects approximately 465 million people worldwide.T. murisis used as a tractable model for the human whipworm. In wild type mice, infection with a high dose ofT. muriseggs leads to worm expulsion, which is dependent on a CD4+Th2 response and interleukin (IL-)13 production. It is known that T cells up-regulate glycolysis and uptake of substrates upon activation. The amino acid transporter SLC7A5 has been shown necessary for activation of mTORC1, a nutrient/energy/redox sensor critical for T cell differentiation into effector cells. We found that at the peak of the immune response toT. muris, mice lacking SLC7A5 in CD4+T cells have delayed worm expulsion, lower levels of IL-13, reduced pmTOR and glycolytic rates. However, at later stages of infection IL-13 levels partially recovered alongside resistance. The critical role of CD4+T cell metabolismper seand down-stream mTOR in CD4+T cells in resistance was shown in mice lacking mTOR in CD4+T cells, that failed to expel a high dose of parasites and developed chronic infection. Our study shows that mTOR is essential for effective functioning of T cells during whipworm infection and that deletion of Slc7a5 significantly delays worm clearance.