bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

AbstractIndole 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.
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

AbstractThe 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

AbstractMuch 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 statementMuch 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

AbstractRecently, 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.
3D DNA structural barcode copying and random access
Authors: Bošković Filip , Ohmann Alexander , Keyser Ulrich F. , Chen Kaikai 
Published: November 2020

AbstractThree-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

ABSTRACTBiomolecular 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

AbstractHumans 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

AbstractFor 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

AbstractIn 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

ABSTRACTEmerging 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

ABSTRACTSynchronous 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

ABSTRACTChloroplast 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

AbstractA 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

SummaryOver 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.