bluuebunny/crossref_metadata_2025 huggingface dataset:
Three-dimensional characterisation of osteocyte volumes at multiple scales, and its relationship with bone biology and genome evolution in ray-finned fishes
Authors: Davesne Donald , Schmitt Armin D. , Fernandez Vincent , Benson Roger B. J. , Sanchez Sophie
Published: September 2019

Osteocytes, cells embedded within the bone mineral matrix, inform on key aspects of vertebrate biology. In particular, a relationship between volumes of the osteocytes and bone growth and/or genome size has been proposed for several tetrapod lineages. However, the variation in osteocyte volume across different scales is poorly characterised, and mostly relies on incomplete, two-dimensional information. In this study, we propose to characterise the variation of osteocyte volumes in ray-finned fishes (Actinopterygii), a clade including more than half of modern vertebrate species in which osteocyte biology is poorly known. We use X-ray synchrotron micro computed tomography (SRμCT) to achieve a three-dimensional visualisation of osteocytes and direct measurement of their volumes. Our specimen sample is designed to characterise osteocyte variation at three scales: within a bone, between the bones of one individual and between taxa spanning actinopterygian phylogeny. At the intra-bone scale, we find that osteocytes vary noticeably in volume between zones of organised and woven bone (being larger in the latter), and across cyclical bone deposition. This is probably explained by differences in bone deposition rate, with larger osteocytes contained in bone that deposits faster. Osteocyte volumes vary from one bone to another, for unclear reasons. Finally, we find that genome size is the best explanatory variable of osteocyte volume at the inter-specific scale: actinopterygian taxa with larger genomes (polyploid taxa in particular) have larger osteocytes. Our findings corroborate previous two-dimensional observations in tetrapods, and open new perspectives for actinopterygian bone evolution, physiology and palaeogenomics.
Simulation with RADinitio Improves RADseq Experimental Design and Sheds Light on Sources of Missing Data
Authors: Rivera-Colón Angel G. , Rochette Nicolas C. , Catchen Julian M.
Published: September 2019

Restriction-site Associated DNA sequencing (RADseq) has become a powerful and versatile tool in modern population genomics, enabling large-scale genomic analyses in otherwise inaccessible biological systems. With its widespread use, different variants on the protocol have been developed to suit specific experimental needs. Researchers face the challenge of choosing the optimal molecular and sequencing protocols for their experimental design, an often-complicated process. Strategic errors can lead to improper data generation that has reduced power to answer biological questions. Here we present RADinitio, simulation software for the selection and optimization of RADseq experiments via the generation of sequencing data that behaves similarly to empirical sources. RADinitio provides an evolutionary simulation of populations, implementation of various RADseq protocols with customizable parameters, and thorough assessment of missing data. Using the software, we test its efficacy using different RAD protocols across several organisms, highlighting the importance of protocol selection on the magnitude and quality of data acquired. Additionally, we test the effects of RAD library preparation and sequencing on allelic dropout, observing that library preparation and sequencing often contributes more to missing alleles than population-level variation.
Distinct features of human myeloid cell cytokine response profiles identify neutrophil activation by cytokines as a prognostic feature during tuberculosis and cancer1
Authors: Devlin Joseph C. , Zwack Erin E. , Tang Mei San , Li Zhi , Fenyo David , Torres Victor J. , Ruggles Kelly V. , Loke P’ng
Published: September 2019

Myeloid cells are a vital component of innate immunity and comprise of monocytes, macrophages, dendritic cells and granulocytes. How myeloid cell lineage affects activation states in response to cytokines remains poorly understood. The cytokine environment and cellular infiltrate during an inflammatory response may contain prognostic features that could predict disease outcome. Here we analyzed the transcriptional responses of human monocytes, macrophages, dendritic cells and neutrophils in response to stimulation by IFN-γ, IFN-β IFN-λ, IL-4, IL-13 and IL-10 cytokines, to better understand the heterogeneity of activation states in inflammatory conditions. This generated a myeloid cell cytokine specific response matrix that can infer representation of myeloid cells and the cytokine environment they encounter during infection and in tumors. Neutrophils were highly responsive to type 1 and type 2 cytokine stimulation but did not respond to IL-10. We identified transcripts specific to IFN-β stimulation, whereas other IFN signature genes were upregulated by both IFN-γ and IFN-β. When we used our matrix to deconvolute blood profiles from tuberculosis patients, the IFN-β specific neutrophil signature was reduced in TB patients with active disease whereas the shared response to IFN-γ and IFN-β in neutrophils was increased. When applied to glioma patients, transcripts of neutrophils exposed to IL-4 or IL-13 and monocyte responses to IFN-γ or IFN-β emerged as opposing predictors of patient survival. Hence, by dissecting how different myeloid cells respond to cytokine activation, we can delineate biological roles for myeloid cells in different cytokine environments during disease processes, especially during infection and tumor progression.
Three-dimensional label-free observation of individual bacteria upon antibiotic treatment using optical diffraction tomography
Authors: Oh Jeonghun , Ryu Jea Sung , Lee Moosung , Jung Jaehwang , Han Seung yun , Chung Hyun Jung , Park Yongkeun
Published: September 2019

Measuring alterations in bacteria upon antibiotic application is important for basic studies in microbiology, drug discovery, and clinical diagnosis, and disease treatment. However, imaging and 3D time-lapse response analysis of individual bacteria upon antibiotic application remain largely unexplored mainly due to limitations in imaging techniques. Here, we present a method to systematically investigate the alterations in individual bacteria in 3D and quantitatively analyze the effects of antibiotics. Using optical diffraction tomography,in-situresponses ofEscherichia coliandBacillus subtilisto various concentrations of ampicillin were investigated in a label-free and quantitative manner. The presented method reconstructs the dynamic changes in the 3D refractive-index distributions of living bacteria in response to antibiotics at sub-micrometer spatial resolution.
An analysis and optimization of growth condition requirements of the fast-growing bacteriumVibrio natriegens
Authors: Örencik Celine , Müller Sara , Kirner Thomas , Amann Egon
Published: September 2019

The fast-growing Gram-negative bacteriumVibrio natriegensis an attractive host for a range of applications in molecular biology and biotechnology. Moreover, the remarkable speed of growth ofVibrio natriegensposes fundamental questions on bacterial physiology and metabolism, energy production, DNA replication and protein synthesis, besides others. In order to address such questions, a solid understanding of the physiological and physical/chemical basis of growth requirements is essential. Here we report a systematic analysis of i) various growth media composition, ii) incubation temperature, iii) pH dependence, and iv) salt concentration requirements for optimal growth ofV. natriegensstrain DSMZ 759. As a result of the studies, the following optimal conditions were Established: LB medium with 2.5 % NaCl, pH 7.0 – 8.5 and incubation at 37°C under aerobic conditions. Incubation temperatures above 37 °C slows growth significantly. Incubation temperatures below 37 °C slows growth, but at a lower rate. Incubation at or below 28 °C should be avoided. Under such optimized, standard laboratory conditions, a doubling time of td= 13.6 minutes was observed forV. natriegensmeasured in mid-log growth phase. The optimized conditions presented here for the growth ofV. natriegenscan be easily applied in any standardly equipped laboratory. For comparison, identical growth conditions forEscherichia coliwere analyzed and are presented as well.

IMPORTANCE

Goal of this study was to understand the physiological growths requirements ofV. natriegensin routine microbiology and molecular biology laboratory settings. The result is a standardized protocol for the optimized growth of the naturally isolated (wild type)V. natriegensstrain DSMZ 759. This protocol can be employed for routine application ofV. natriegensfor any kind of biochemical, molecular biology and genomic studies and utilization under normal laboratory conditions used by many routinely equipped laboratories.
Forging new antibiotic combinations under iron-limiting conditions
Authors: Chan Derek C. K. , Guo Irene , Burrows Lori L.
Published: September 2019

Pseudomonas aeruginosais a multidrug-resistant nosocomial pathogen. We showed previously that thiostrepton (TS), a gram-positive thiopeptide antibiotic, was imported via pyoverdine receptors and synergized with iron chelator deferasirox (DSX) to inhibit the growth ofP. aeruginosaandAcinetobacter baumanniiclinical isolates. A small number ofP. aeruginosaandA. baumanniiisolates were resistant to the combination, prompting us to search for other compounds that could synergize with TS against those strains. From literature surveys we selected 14 compounds reported to have iron-chelating activity, plus one iron analogue, and tested them for synergy with TS. Doxycycline (DOXY), ciclopirox olamine (CO), tropolone (TRO), clioquinol (CLI), and gallium nitrate (GN) synergized with TS. Individual compounds were bacteriostatic but the combinations were bactericidal. Our spectrophotometric data and chrome azurol S agar assay confirmed that the chelators potentate TS activity through iron sequestration rather than through their innate antimicrobial activities. A triple combination of TS + DSX + DOXY had the most potent activity againstP. aeruginosaandA. baumanniiisolates. OneP. aeruginosaclinical isolate was resistant to the triple combination, but susceptible to a triple combination containing higher concentrations of CLI, CO, or DOXY. AllA. baumanniiisolates were susceptible to the triple combinations. Our data reveal a diverse set of compounds with dual activity as antibacterial agents and TS adjuvants, allowing combinations to be tailored for resistant clinical isolates.
Optimal response to quorum-sensing signals varies in different host environments with different pathogen group size
Authors: Zhou Liqin , Slamti Leyla , Lereclus Didier , Raymond Ben
Published: September 2019

The persistence of genetic variation in master regulators of gene expression, such as quorum-sensing systems, is hard to explain. Here, we investigated two alternative hypotheses for the prevalence of polymorphic quorum-sensing in Gram-positive bacteria,i.e. the use of different signal / receptor pairs (‘pherotypes’) to regulate the same functions. First, social interactions between pherotypes or ‘facultative cheating’ may favour rare variants that exploit the signals of others. Second, different pherotypes may increase fitness in different environments. We evaluated these hypotheses in the invertebrate pathogenBacillus thuringiensis, using three pherotypes expressed in a common genetic background. Facultative cheating occurred in homogenized hosts, in contrast, rare pherotypes had reduced fitness in naturalistic infections. There was clear support for environment-dependent fitness: pherotypes varied in responsiveness to signals and in mean competitive fitness. Notably, competitive fitness varied with group size: the pherotype with highest responsiveness to signals performed best in smaller hosts where infections have a lower pathogen group size. Less responsive pherotypes performed best in larger hosts. Results using homogenized insect media fit with the expectation of facultative cheating and social evolution theory, but results from naturalist oral infections do not fit many of the predictions from this body of theory. In this system, low signal abundance appears to limit fitness in hosts while the optimal level of response to signals varies in different host environments.

Importance

Quorum sensing describes the ability of microbes to alter gene regulation according to their local population size. Some successful theory suggests that this is a form of cooperation: investment in shared products is only worthwhile if there are sufficient bacteria making the same product. This theory can explain the genetic diversity in these signaling systems in Gram-positive bacteria such asBacillusandStaphylococcus. The possible advantages gained by rare genotypes (which can exploit the products of their more common neighbours) could explain why different genotypes can coexist. We show that while these social interactions can occur in simple laboratory experiments they do not occur in naturalistic infections using an invertabrate pathogen,Bacillus thuringiensis. Instead our results suggest that different genotypes are adapted to different-sized hosts. Overall, social models are not easily applied to this system implying that a new explanation for this form of quorum sensing is required.
Dual UTR-A novel 5′ untranslated region design for synthetic biology applications
Authors: Le Simone Balzer , Onsager Ingerid , Lorentzen Jon Andreas , Lale Rahmi
Published: September 2019

Bacterial 5′ untranslated regions of mRNA (UTR) involve in a complex regulation of gene expression; however, the exact sequence features contributing to gene regulation are not yet fully understood. In this study, we report the design of a novel 5′ UTR, dual UTR, utilising the transcriptional and translational characteristics of 5′ UTRs in a single expression cassette. The dual UTR consists of two 5′ UTRs, each separately leading to either increase in transcription or translation of the reporter, that are separated by a spacer region, enabling de novo translation initiation. We rationally create dual UTRs with a wide range of expression profiles and demonstrate the functionality of the novel design concept in Escherichia coli and in Pseudomonas putida using different promoter systems and coding sequences. Overall, we demonstrate the application potential of dual UTR design concept in various synthetic biology applications ranging from fine-tuning of gene expression to maximisation of protein production.
Programmed Cell Death in the Developing Brachypodium distachyon Grain
Authors: Saada Safia , Solomon Charles Ugochukwu , Drea Sinéad
Published: September 2019

The normal developmental sequence in a grass grain entails the death of several maternal and filial tissues in a genetically regulated process termed programmed cell death (PCD). The progression and molecular aspects of PCD in developing grain have been reported for domesticated species like barley, rice, maize and wheat. Here, we report a detailed investigation of PCD in the developing grain of a wild model species, Brachypodium distachyon.

We detected PCD in developing Brachypodium grains using molecular and histological approaches. We also identified and surveyed the expression of Brachypodium orthologs of protease genes known to contribute to grain PCD.

We found that Brachypodium nucellus degenerates by PCD in a centrifugal pattern following anthesis, although at a slower rate compared to cultivated cereals. Mesocarp PCD was not coordinated with endosperm development. Brachypodium lacks an expansion of vacuolar processing enzymes known for their roles in nucellar PCD.

Combined with existing knowledge on grain PCD, our study suggests the importance of rapid nucellar PCD for grain size and that the pattern of mesocarp PCD affects grain shape.
Mechanistic macroecology: exploring the drivers of latitudinal variation in terrestrial body size in a General Ecosystem Model
Authors: Harfoot Michael Brian James , Abraham Andrew , Tittensor Derek P , Costa Gabriel C , Faurby Søren , Feldman Anat , Itescu Yuval , Meiri Shai , Morales-Castilla Ignacio , Oliveira Brunno F , Purves Drew
Published: September 2019

Many mechanisms have been hypothesized to explain Bergmann’s rule - the correlation of body size with latitude. However, it is not feasible to assess the contribution of hypothesised mechanisms by experimental manipulation or statistical correlation. Here, we evaluate two of the principal hypothesised mechanisms, related to thermoregulation and resource availability, using structured experiments in a mechanistic global ecosystem model. We simulated the broad structure of assemblages and ecosystems using the Madingley model, a mechanistic General Ecosystem Model (GEM). We compared emergent modelled biogeographic patterns in body mass to empirical patterns for mammals and birds. We then explored the relative contribution of thermoregulation and resource availability to body mass clines by manipulating the model’s environmental gradients. Madingley produces body size gradients that are in broad agreement with empirical estimates. Thermoregulation and resource availability were both important controls on body mass for endotherms, but only temperature for ectotherms. Our results suggest that seasonality explains animal body mass patterns through a complex set of mechanisms. Process-based GEMs generate broadly realistic biogeographic body mass patterns. Ecologists can use them in novel ways: to explore causality, or for generating and testing hypotheses for large-scale, emergent ecological patterns. At the same time, macroecological patterns are useful for evaluating mechanistic models. Iteratively developing GEMs, and evaluating them against macroecological patterns, could generate new insights into the complex causes of such patterns.
OTULIN protects the liver against cell death, inflammation, fibrosis, and cancer
Authors: Damgaard Rune Busk , Jolin Helen E. , Allison Michael E.D. , Davies Susan E. , McKenzie Andrew N.J. , Komander David
Published: September 2019

The deubiquitinase OTULIN removes methionine-1 (M1)-linked polyubiquitin chains to regulate TNF-mediated inflammation and cell death, but the physiological role of OTULIN outside the immune system is poorly understood. Here, we identify OTULIN as a liver tumour suppressor in mice. Hepatocyte-specific OTULIN deletion causes spontaneous steatohepatitis, extensive fibrosis, and pre-malignant tumours by eight weeks of age, which progresses to hepatocellular carcinoma by 7-12 months. OTULIN deficiency triggers apoptosis and inflammation in the liver, but surprisingly, steatohepatitis and pre-malignant growth is independent of TNFR1 signalling. Instead, the pathology in OTULIN-deficient livers is associated with increased mTOR activation, and mTOR inhibition with rapamycin reduces fibrosis and pre-malignant growth. This demonstrates that OTULIN is critical for maintaining liver homeostasis and preventing mTOR-driven liver disease.
Responses to heartbeats in ventromedial prefrontal cortex contribute to subjective preference-based decisions
Authors: Azzalini Damiano , Buot Anne , Palminteri Stefano , Tallon-Baudry Catherine
Published: September 2019

Forrest Gump or Matrix? Preference-based decisions are subjective and entail self-reflection. However, these self-related features are unaccounted for by known neural mechanisms of valuation and choice. Self-related processes have been linked to a basic interoceptive biological mechanism, the neural monitoring of heartbeats, in particular in ventromedial prefrontal cortex (vmPFC), a region also involved in value encoding. We thus hypothesized a functional coupling between the neural monitoring of heartbeats and the precision of value encoding in vmPFC. Human participants were presented with pairs of movie titles. They indicated either which movie they preferred, or performed a control objective visual discrimination that did not require self-reflection. Using magnetoencephalography, we measured heartbeat-evoked responses (HERs) before option presentation, and confirmed that HERs in vmPFC were larger when preparing to the subjective, self-related task. We retrieved the expected cortical value network during choice with time-resolved statistical modeling. Crucially, we show that larger HERs before option presentation are followed by stronger value encoding during choice in vmPFC. This effect is independent of the overall vmPFC baseline activity. The neural interaction between HERs and value encoding predicted preference-based choice consistency over time, accounting for both inter-individual differences and trial-to-trial fluctuations within individuals. Neither cardiac activity nor arousal fluctuations could account for any of the effects. HERs did not interact with the encoding of perceptual evidence in the discrimination task. Our results show that the self-reflection underlying preference-based decisions involves the integration of HERs to subjective value encoding in vmPFC, and that this integration contributes to preference stability.

Significance statement

Deciding whether you prefer Forrest Gump or Matrix is based on subjective values, which only you, the decision-maker, can estimate and compare, by asking yourself. Yet, how self-reflection is biologically implemented and its contribution to subjective valuation are not known. We show that in ventromedial prefrontal cortex, the neural response to heartbeats, an interoceptive self-related process, influences the cortical representation of subjective value. The neural interaction between the cortical monitoring of heartbeats and value encoding predicts choice consistency, i.e. whether you consistently prefer Forrest Gump over Matrix over time. Our results pave the way for the quantification of self-related process in decision making and may shed new light on the relationship between maladaptive decisions and impaired interoception.
A sex chromosome inversion is associated with copy number variation of mitochondrial DNA in zebra finch sperm
Authors: Knief Ulrich , Forstmeier Wolfgang , Kempenaers Bart , Wolf Jochen B. W.
Published: September 2019

Propulsion of sperm cells via movement of the flagellum is of vital importance for successful fertilization. Presumably, the energy for this movement comes from the mitochondria in the sperm midpiece. Larger midpieces may contain more mitochondria, which should enhance the energetic capacity and hence promote mobility. Due to an inversion polymorphism on their sex chromosome TguZ, zebra finches (Taeniopygia guttata castanotis) exhibit large within-species variation in sperm midpiece length, and those sperm with the longest midpieces swim the fastest. Here, we test through quantitative real-time PCR in zebra finch ejaculates whether the inversion genotype has an effect on the copy number of mitochondrial DNA. Taking the inversion genotype as a proxy for midpiece length, we find that zebra finches with longer midpieces indeed have more copies of the mitochondrial DNA in their ejaculates than those with shorter midpieces, with potential downstream effects on the rate of ATP production and sperm swimming speed. This study sheds light on the proximate cause of a fitness-relevant genetic polymorphism, suggesting the involvement of central components of gamete energy metabolism.

Data availability

Supplementary data file
Structural Basis of Protein Arginine Methyltransferase Activation by a Catalytically Dead Homolog (Prozyme)
Authors: Hashimoto Hideharu , Kafková Lucie , Raczkowski Ashleigh , Jordan Kelsey , Read Laurie K. , Debler Erik W.
Published: September 2019

Prozymes are pseudoenzymes that stimulate the function of weakly active enzymes through complex formation. The majorTrypanosoma bruceiprotein arginine methyltransferase,TbPRMT1 enzyme (ENZ), requiresTbPRMT1 prozyme (PRO) to form an active heterotetrameric complex. Here we present the x-ray crystal structure of the ENZ-Δ52PRO tetrameric complex with the cofactor product S-adenosyl-L-homocysteine (AdoHcy) at 2.4 Å resolution. The individual ENZ and PRO units adopt the highly-conserved PRMT domain architecture and form an antiparallel heterodimer that corresponds to the canonical homodimer observed in all previously reported PRMTs. In turn, two such heterodimers assemble into a tetramer both in the crystal and in solution with twofold rotational symmetry. ENZ is unstable in absence of PRO and incapable of forming a homodimer due to a steric clash of a non-conserved tyrosine within the dimerization arm, rationalizing why PRO is required to complement ENZ to form a PRMT dimer that is necessary, but not sufficient for PRMT activity. The PRO structure deviates from other, active PRTMs in that it lacks the conserved η2 310-helix within the Rossmann fold, abolishing co-factor binding. In addition to its chaperone function for ENZ, PRO substantially contributes to substrate binding. Heterotetramerization is required for catalysis, since heterodimeric ENZ-PRO mutants lack binding affinity and methyltransferase activity towards the substrate proteinTbRGG1. Together, we provide a structural basis for PRMT1 ENZ activation by PRO heterotetramer formation, which is conserved across all kinetoplastids, and describe a chaperone function of the PRMT1 prozyme, which represents a novel mode of PRMT regulation.

Graphical Abstract

Highlights

The crystal structure ofTrypanosoma bruceiprotein arginine methyltransferase 1 (PRMT1) is reported

Two enzyme-prozyme heterodimers form a stable heterotetramer essential for catalysis

The catalytically dead prozyme lacks elements essential for AdoMet binding

The enzyme alone is unstable and cannot form a canonical dimer due to steric clashes

T. bruceiPRMT1 prozyme adopts a chaperone function conserved across kinetoplastids
Minimally disruptive optical control of protein tyrosine phosphatase 1B
Authors: Hongdusit Akarawin , Zwart Peter H. , Sankaran Banumathi , Fox Jerome M.
Published: September 2019

Protein tyrosine phosphatases regulate a myriad of essential subcellular signaling events, yet they remain difficult to study in their native biophysical context. Here we develop a minimally disruptive optical approach to control protein tyrosine phosphatase 1B (PTP1B)—an important regulator of receptor tyrosine kinases and a therapeutic target for the treatment of diabetes, obesity, and cancer—and we use that approach to probe the intracellular function of this enzyme. Our conservative architecture for photocontrol, which consists of a protein-based light switch fused to an allosteric regulatory element, preserves the native structure, activity, and subcellular localization of PTP1B, affords changes in activity that match those elicited by post-translational modifications inside the cell, and permits experimental analyses of the molecular basis of optical modulation. Findings indicate, most strikingly, that small changes in the activity of PTP1B can cause large shifts in the phosphorylation states of its regulatory targets.
Robust effects of corticothalamic feedback and behavioral state on movie responses in mouse dLGN
Authors: Spacek Martin A. , Crombie Davide , Bauer Yannik , Born Gregory , Liu Xinyu , Katzner Steffen , Busse Laura
Published: September 2019

Neurons in the dorsolateral geniculate nucleus (dLGN) of the thalamus receive a substantial proportion of modulatory inputs from corticothalamic (CT) feedback and brain stem nuclei. Hypothesizing that these modulatory influences might be differentially engaged depending on the visual stimulus and behavioral state, we performed in vivo extracellular recordings from mouse dLGN while optogenetically suppressing CT feedback and monitoring behavioral state by locomotion and pupil dilation. For naturalistic movie clips, we found CT feedback to consistently increase dLGN response gain and promote tonic firing. In contrast, for gratings, CT feedback effects on firing rates were mixed. For both stimulus types, the neural signatures of CT feedback closely resembled those of behavioral state, yet effects of behavioral state on responses to movies persisted even when CT feedback was suppressed. We conclude that CT feedback modulates visual information on its way to cortex in a stimulus-dependent manner, but largely independently of behavioral state.
Young children combine sensory cues with learned information in a statistically efficient manner: But task complexity matters
Authors: Bejjanki Vikranth R. , Randrup Emily R. , Aslin Richard N.
Published: September 2019

Human adults are adept at mitigating the influence of sensory uncertainty on task performance by integrating sensory cues with learned prior information, in a Bayes-optimal fashion. Previous research has shown that young children and infants are sensitive to environmental regularities, and that the ability to learn and use such regularities is involved in the development of several cognitive abilities. However, it has also been reported that children younger than 8 do not combine simultaneously available sensory cues in a Bayes-optimal fashion. Thus, it remains unclear whether, and by what age, children can combine sensory cues with learned regularities in an adult manner. Here, we examine the performance of 6-7-year old children when tasked with localizing a ‘hidden’ target by combining uncertain sensory information with prior information learned over repeated exposure to the task. We demonstrate that 6-7-year olds learn task-relevant statistics at a rate on-par with adults, and like adults, are capable of integrating learned regularities with sensory information in a statistically efficient manner. We also show that variables such as task complexity can influence young children’s behavior to a greater extent than that of adults, leading their behavior to look sub-optimal. Our findings have important implications for how we should interpret failures in young children’s ability to carry out sophisticated computations. These ‘failures’ need not be attributed to deficits in the fundamental computational capacity available to children early in development, but rather to ancillary immaturities in general cognitive abilities that mask the operation of these computations in specific situations.

Research Highlights

Young children are sensitive to, and can learn, environmental regularities. Can they also utilize such learned regularities in a statistically efficient manner?

We demonstrate that 6-7-year olds are capable of learning and utilizing regularities in a statistically efficient fashion, and in a manner indistinguishable from adult behavior.

However, variables such as task complexity can influence young children’s behavior to a greater extent than that of adults, leading their behavior to look sub-optimal.

These findings have important implications for how we should interpret failures in young children’s ability to carry out sophisticated computations.
nkx3.2mutant zebrafish accommodate jaw joint loss through a phenocopy of the head shapes of Paleozoic jawless fish
Authors: Miyashita Tetsuto , Baddam Pranidhi , Smeeton Joanna , Oel Adam Phillip , Natarajan Natasha , Gordon Brogan , Palmer A. Richard , Crump Gage , Graf Daniel , Allison W. Ted
Published: September 2019

The vertebrate jaw is a versatile feeding apparatus that facilitated explosive diversification. To function, it requires a joint between the upper and lower jaws, so jaw joint defects - such as osteoarthritis or even ankylosis - are often highly disruptive and difficult to study. To describe consequences of jaw-joint dysfunction, we engineered two independent null alleles of a single jaw-joint marker gene,nkx3.2, in zebrafish. These mutations caused zebrafish to become functionally jawless via fusion of the upper and lower jaw cartilages (ankylosis). Despite lacking jaw joints,nkx3.2mutants survive to adulthood and accommodate this defect by: a) remodeling their skulls; and b) altering their behavior from suction feeding to ram feeding. As a result of remodeling,nkx3.2mutants developed superficial similarities to the skull shapes observed in two lineages of ancient jawless vertebrates (anaspids and furcacaudiid thelodonts), including: a fixed open gape, reduced snout, and enlarged branchial region. However, no homology exists in individual skull elements between these taxa, and most of the modified elements in the mutant zebrafish occur outside known expression domains ofnkx3.2. Therefore, we interpret the adultnkx3.2phenotype not as a reversal to an ancestral state, but as convergence due to similar functional requirement of feeding without moveable jaws. This remarkable convergence strongly suggests that jaw movements themselves dramatically influence the development of jawed vertebrate skulls, which implies that functionally viable skull morphologies are finite, with or without functional jaws. Becausenkx3.2null zebrafish display prominent joint ankylosis, drastically modified skull shape, and altered feeding behaviors, these mutants provide a unique model with which to investigate mechanisms of skeletal remodeling and joint diseases.
Pathways of human development threaten biomes’ protection and their remaining natural vegetation
Authors: Rosa Isabel M.D. , Guerra Carlos A.
Published: September 2019

Protected areas have been one of the most commonly applied conservation tools to prevent ecosystem degradation. International conservation targets have been created to incentivize widespread expansion of protected area networks, but this call might clash with expected future land use change. Here we investigated how future land use trajectories (2015-2090), representing a wide range of plausible future scenarios would impact the remaining areas of primary vegetation under different protection levels across the world’s biomes. We then highlight areas under greater risk of conflict between conservation (highly protected) and land use expansion (high projected change), and areas where these two can better co-exist (lower protection with high projected change and/or high protection with low projected change).

While the most positive pathway of development led to the least loss of primary vegetation globally, this was not observed in all biomes. Further, we found no significant correlation between existing extent of protection and average proportion of vegetation loss. Mediterranean Forests, Woodlands & Scrub had the largest projected loss occurring in the highest protected areas. Tropical Forests in Central Africa and the Boreal Forests of North Euro-Asia and Canada emerge as the areas where most projected change occurs, and existing protection is still low. Areas in India and Southeast Asia emerge as potential areas for intervention as they have significant projected loss of primary vegetation, and considerably low protection.

Our results can help inform policy and decision-makers to prevent such conflicts and support the development of management actions. These policy and management actions should target conservation in areas under expected great pressure of change with high ecological value (e.g., composed mainly by primary vegetation), but still not protected. This study also opens the discussion to the future of current protected areas and to the potential to expand the existing network of protected areas.
Evolution rapidly optimizes stability and aggregation in lattice proteins despite pervasive landscape valleys and mazes
Authors: Bertram Jason , Masel Joanna
Published: September 2019

Fitness landscapes are widely used to visualize the dynamics and long-term outcomes of evolution. The fitness landscapes of genetic sequences are characterized by high dimensionality and “ruggedness” due to sign epistasis. Ascending from low to high fitness on such landscapes can be difficult because adaptive trajectories get stuck at low-fitness local peaks. Compounding matters, recent computational complexity arguments have proposed that extremely long, winding adaptive paths may be required to even reach local peaks, a “maze-like” landscape topography. The extent to which peaks and mazes shape the mode and tempo of evolution is poorly understood due to empirical limitations and the abstractness of many landscape models. We develop a biophysically-grounded computational model of protein evolution based on two novel extensions of the classic hydrophobic-polar lattice model of protein folding. First, rather than just considering fold stability we account for the tradeoff between stability and aggregation propensity. Second, we use a “hydrophobic zipping” algorithm to kinetically generate ensembles of post-translationally folded structures. Our stability-aggregation fitness landscape exhibits extensive sign epistasis and local peaks galore. We confirm the postulated existence of maze-like topography in our biologically-grounded landscape. Although these landscape features frequently obstruct adaptive ascent to high fitness and virtually eliminate reproducibility of evolutionary outcomes, many adaptive paths do successfully complete the long ascent from low to high fitness. This delicate balance of “hard but possible” adaptation could occur more broadly provided that the optimal outcomes possible under a tradeoff are improved by rare constraint-breaking substitutions.
Differential modulation of ventral tegmental area circuits by the nociceptin/orphanin FQ system
Authors: Driscoll Joseph R. , Wallace Tanya L. , Mansourian Kasra A. , Martin William J. , Margolis Elyssa B.
Published: September 2019

The neuropeptide nociceptin/orphanin FQ (N/OFQ) can be released by stressors and is associated with disorders of emotion regulation and reward processing. N/OFQ and its receptor, NOP, are enriched in dopaminergic pathways, and intra-ventricular agonist delivery decreases dopamine levels in the dorsal striatum, nucleus accumbens (NAc), and ventral tegmental area (VTA). We used whole cell electrophysiology in acute rat midbrain slices to investigate synaptic actions of N/OFQ. N/OFQ was primarily inhibitory, causing outward currents in both immunocytochemically identified dopaminergic (tyrosine hydroxylase positive (TH(+)) and non-dopaminergic (TH(−)) VTA neurons (effect at 1 μM: 20 ± 4 pA). Surprisingly, this effect was mediated by augmentation of postsynaptic GABAAR currents, unlike the substantia nigra pars compacta (SNc), where the N/OFQ induced outward currents were K+ channel dependent. A smaller population, 19% of all VTA neurons, responded to low concentrations N/OFQ with inward currents (10 nM: −11 ± 2 pA). Following 100 nM N/OFQ, the response to a second N/OFQ application was markedly diminished in VTA neurons (14 ± 10% of first response), but not in SNc neurons (90 ± 20% of first response). N/OFQ generated outward currents in medial prefrontal cortex (mPFC)-projecting VTA neurons, but inward currents in a subset of posterior anterior cingulate cortex-projecting VTA neurons. While N/OFQ inhibited NAc-projecting VTA cell bodies, it had little effect on electrically or optogenetically evoked terminal dopamine release in the NAc measured ex vivo with fast scan cyclic voltammetry. These results extend our understanding of the N/OFQ system in brainstem circuits implicated in many neurobehavioral disorders.

Significance statement

The neuropeptide nociceptin/orphanin FQ (N/OFQ) and its receptor (NOP) are engaged under conditions of stress and are associated with reward processing disorders. Both peptide and receptor are highly enriched in ventral tegmental area (VTA) pathways underlying motivation and reward. Using whole cell electrophysiology in rat midbrain slices we found: 1) NOPs are functional on both dopaminergic and non-dopaminergic VTA neurons; 2) N/OFQ differentially regulates VTA neurons based on neuroanatomical projection target; and 3) repeated application of N/OFQ produces evidence of receptor desensitization in the VTA but not the SNc. These results reveal candidate mechanisms by which the NOP system regulates motivation and emotion.
Evaluating the Probability of CRISPR-based Gene Drive Contaminating Another Species
Authors: Courtier-Orgogozo Virginie , Danchin Antoine , Gouyon Pierre-Henri , Boëte Christophe
Published: September 2019

The probability D that a given CRISPR-based gene drive element contaminates another, non-target species can be estimated by the following Drive Risk Assessment Quantitative Estimate (DRAQUE) Equation:

D = (hyb+transf).express.cut.flank.immune.nonextinctwith

hyb= probability of hybridization between the target species and a non-target species

transf= probability of horizontal transfer of a piece of DNA containing the gene drive cassette from the target species to a non-target species (with no hybridization)

express= probability that theCas9and guide RNA genes are expressed

cut= probability that the CRISPR-guide RNA recognizes and cuts at a DNA site in the new host

flank= probability that the gene drive cassette inserts at the cut site

immune= probability that the immune system does not rejectCas9-expressing cells

nonextinct= probability of invasion of the drive within the population

We discuss and estimate each of the seven parameters of the equation, with particular emphasis on possible transfers within insects, and between rodents and humans. We conclude from current data that the probability of a gene drive cassette to contaminate another species is not insignificant. We propose strategies to reduce this risk and call for more work on estimating all the parameters of the formula.
Nest microbiota and pathogen abundance impact hatching success in sea turtle conservation
Authors: Hoh Daphne Z , Lin Yu-Fei , Liu Wei-An , Sidique Siti Nordahliawate Mohamed , Tsai Isheng Jason
Published: September 2019

Hatchery practices are pivotal to conservation success. In sea turtle hatchery, reusing the same sand has been a norm but remains unclear whether such approach increases the risk ofFusarium solanispecies complex (FSSC) infection causing huge mortality in sea turtle eggs worldwide. We employed 16S and ITS amplicon sequencing in 123 sand samples and isolated fungal strains from diseased eggs across seven hatcheries and neighboring beaches in Malaysia. FSSC was isolated from all sampled hatcheries whereF. solani/falciformewas the predominant species. A distinct microbial composition and higher abundance of FSSC (mean = 5.2 %) was found in all but one hatchery when compared to nesting beaches (mean = 1.3 %). Specifically, an ascomycetous fungusPseudallescheria boydiiconsistently appeared in higher abundance (mean = 11.4 %) in FSSC-infected nests and was significantly associated with lower hatching success. The hatchery that maintained the most stringent practice by changing sand every nesting season had a microbiota resembling nesting beaches as well as lowest FSSC andP. boydiiabundance. The results of current study imply the need to avoid reusing sand in sea turtle hatchery.
Spatial whitening in the retina may be necessary for V1 to learn a sparse representation of natural scenes
Authors: Dodds Eric McVoy , Livezey Jesse Alexander , DeWeese Michael Robert
Published: September 2019

Retinal ganglion cell outputs are less correlated across space than are natural scenes, and it has been suggested that this decorrelation is performed in the retina in order to improve efficiency and to benefit processing later in the visual system. However, sparse coding, a successful computational model of primary visual cortex, is achievable under some conditions with highly correlated inputs: most sparse coding algorithms learn the well-known sparse features of natural images and can output sparse, high-fidelity codes with or without a preceding decorrelation stage of processing. We propose that sparse coding with biologically plausible local learning rules does require decorrelated inputs, providing a possible explanation for why whitening may be necessary early in the visual system.
The source of additive genetic variance of evolutionarily important traits
Authors: Liu Li , Wang Yayu , Zhang Di , Chen Xiaoshu , Su Zhijian , He Xionglei
Published: September 2019

Fisher’s fundamental theorem of natural selection predicts no additive variance of fitness in a natural population. Consistently, observations in a variety of wild populations show virtually no narrow-sense heritability (h2) for traits important to fitness. However, counterexamples are occasionally reported, calling for a deeper understanding on the evolution of additive variance. In this study we propose adaptive divergence followed by population admixture as a source of the additive genetic variance of evolutionarily important traits. We experimentally tested the hypothesis by examining a panel of ~1,000 yeast segregants produced by a hybrid of two yeast strains that experienced adaptive divergence. We measured over 400 yeast cell morphological traits and found a strong positive correlation between h2 and evolutionary importance. Because adaptive divergence followed by population admixture could happen constantly, particularly in some species such as humans, the finding reconciles the observation of abundant additive variances in evolutionarily important traits with Fisher’s fundamental theorem of natural selection. It also suggests natural selection may effectively promote rather than suppress additive genetic variance in species with wide geographic distribution and strong migratory capacity.
Short residence times of DNA-bound transcription factors can reduce gene expression noise and increase the transmission of information in a gene regulation system
Authors: Azpeitia Eugenio , Wagner Andreas
Published: September 2019

Gene expression noise is not just ubiquitous but also variable, and we still do not understand some of the most elementary factors that affect it. Among them is the residence time of a transcription factor (TF) on DNA, the mean time that a DNA-bound TF remains bound. Here, we use a stochastic model of transcriptional regulation to study how this residence time affects gene expression. We find that the effect of residence time on gene expression depends on the level of induction of the gene. At high levels of induction, residence time has no effect on gene expression. However, as the level of induction decreases, short residence times reduce gene expression noise. The reason is that fast on-off TF binding dynamics prevent long periods where proteins are predominantly synthesized or degraded, which can cause excessive fluctuations in gene expression. As a consequence, short residence times can help a gene regulation system acquire information about the cellular environment it operates in. Our predictions are consistent with the observation that experimentally measured residence times are usually modest and lie between seconds to minutes.
Structural characterization of a prolyl aminodipeptidase (PepX) from Lactobacillus helveticus
Authors: Ojennus Deanna Dahlke , Bratt Nicholas J. , Jones Kent L. , Juers Douglas H.
Published: September 2019

Prolyl aminodipeptidase (PepX) is an enzyme that hydrolyzes peptide bonds from the N-terminus of substrates when the penultimate amino-acid residue is a proline. Prolyl peptidases are of particular interest owing to their ability to hydrolyze food allergens that contain a high percentage of proline residues. PepX from Lactobacillus helveticus was cloned and expressed in Escherichia coli as an N-terminally His-tagged recombinant construct and was crystallized by hanging-drop vapor diffusion in a phosphate buffer using PEG 3350 as a precipitant. The structure was determined at 2.0 Å resolution by molecular replacement using the structure of PepX from Lactococcus lactis (PDB entry 1lns) as the starting model. Notable differences between the L. helveticus PepX structure and PDB entry 1lns include a cysteine instead of a phenylalanine at the substrate-binding site in the position which confers exopeptidase activity and the presence of a calcium ion coordinated by a calcium-binding motif with the consensus sequence DX(DN)XDG.