bluuebunny/crossref_metadata_2025 huggingface dataset:
Synthesis of novel technetium-99m tricarbonyl-HBED-CC complexes and structural prediction in solution by density functional theory calculation
Authors: Shi Shengyu , Yao Lifeng , Li Linlin , Wu Zehui , Zha Zhihao , Kung Hank F. , Zhu Lin , Fang De-Cai
Published: November 2019

HBED-CC (
N,N'
-bis[2-hydroxy-5-(carboxyethyl)benzyl]ethylene diamine-
N,N'
-diacetic acid,

L
1

) is a common bifunctional chelating agent in preparation of
68
Ga-radiopharmaceuticals. Due to its high stability constant for the Ga
3+
complex (logK
GaL
= 38.5) and its acyclic structure, it is well known for a rapid and efficient radiolabelling at ambient temperature with Gallium-68 and its high
in vivo
stability. [
99m
Tc][Tc(CO)
3
(H
2
O)
3
]
+
is an excellent precursor for radiolabelling of biomolecules. The aim of this study was to develop a novel preparation method of
99m
Tc-HBED-CC complexes. In this study, HBED-CC-NI (2,2'-(ethane-1,2-diylbis((2-hydroxy-5-(3-((2-(2-nitro-1H-imidazol-1-yl)ethyl)amino)-3-oxopropyl)benzyl)-azanediyl))-diacetic acid,

L
2

), a derivative of HBED-CC, was designed and synthesized. Both

L
1

and

L
2

were radiolabelled by [
99m
Tc][Tc(CO)
3
(H
2
O)
3
]
+
successfully for the first time. In order to explore the coordination mode of metal and chelates, non-radioactive Re(CO)
3

L
1

and Re(CO)
3

L
2

were synthesized and characterized spectroscopically. Tc(CO)
3

L
1

and Tc(CO)
3

L
2

in solution were calculated by density functional theory and were analysed with radio-HPLC chromatograms. It showed that [
99m
Tc]Tc(CO)
3

L
2

forms two stable diastereomers in solution, which is similar to those of [
68
Ga]Ga-HBED-CC complexes. Natural bond orbital analysis through the natural population charges revealed a charge transfer between [
99m
Tc][Tc(CO)
3
]
+
and

L
1

or

L
2

. The experimental results showed that tricarbonyl technetium might form stable complex with HBED-CC derivatives, which is useful for the future application of using HBED-CC as a bifunctional chelating agent in developing new
99m
Tc-radiopharmaceuticals as diagnostic imaging agents.
Predicting maths anxiety from mathematical achievement across the transition from primary to secondary education
Authors: Field Andy P. , Evans Danielle , Bloniewski Tomasz , Kovas Yulia
Published: November 2019

The primary- to secondary-education transition is a substantive life event for many children. The transition can be associated with changes in the developmental trajectories of both emotional health and academic achievement. The current study looked at whether the trajectory of mathematical attainment and emotional health (anxiety) across this transition predicted later maths anxiety. A secondary analysis of data from the Twin Early Development Study (TEDS) was performed. The statistical models were fit on the 753 participants (one from each twin pair) for which there were measures of mathematical performance across the primary- to secondary-education transition and maths anxiety at age 18. Two multi-level growth models were fit predicting mathematical attainment and anxiety over the primary- to secondary-education transition. The intercepts and slopes for each child were extracted from these models and used as predictors of subsequent maths anxiety at age 18. These effects were adjusted for biological sex, socio-economic status, verbal cognitive ability and general anxiety. Maths anxiety at age 18 was significantly predicted by both pre-transition levels of anxiety and mathematical attainment and their rate of change across the primary- to secondary-education transition. However, the effects were small, suggesting that theories of maths anxiety may have overplayed the role of prior mathematical attainment and general anxiety.
The complex evolutionary history of sulfoxide synthase in ovothiol biosynthesis
Authors: Gerdol Marco , Sollitto Marco , Pallavicini Alberto , Castellano Immacolata
Published: November 2019

Sulfoxide synthases are enzymes involved in the biosynthesis of small sulfur-containing natural products. Their enzymatic activity represents a unique sulfur transfer strategy in nature that is the insertion of a sulfur atom on the imidazole ring of histidine. To date, only two enzymes are known to carry out this function: the sulfoxide synthase EgtB, involved in the biosynthesis of ergothioneine in fungi and bacteria, and the 5-histidylcysteine sulfoxide synthase OvoA, involved in the biosynthesis of ovothiols, found in the eggs and biological fluids of marine invertebrates, some proteobacteria and protists. In particular, ovothiols, thanks to their unique redox properties, are probably the most intriguing marine sulfur-containing molecules. Although they have long been considered as cellular protective molecules, new evidence suggest that their biological activities and ecological role might be more complex than originally thought. Here, we investigate the evolutionary history of OvoA in Metazoa, reporting its monophyletic ancient origins, which could be traced back to the latest common ancestor of Choanozoa. Nevertheless, we show that OvoA is missing in several major extant taxa and we discuss this patchy distribution in the light of the massive genome reduction events documented in Metazoa. We also highlight two interesting cases of secondary acquisition through horizontal gene transfer, which occurred in hydrozoans and bdelloid rotifers. The evolutionary success of this metabolic pathway is probably ascribable to its role in the maintenance of cellular redox homeostasis, which enables organisms to survive in different environmental niches.
An X-linked meiotic drive allele has strong, recessive fitness costs in femaleDrosophila pseudoobscura
Authors: Larner William , Price Tom , Holman Luke , Wedell Nina
Published: November 2019

Selfish ‘meiotic drive’ alleles are transmitted to more than 50% of offspring, allowing them to rapidly invade populations even if they reduce the fitness of individuals carrying them. Theory predicts that drivers should either fix or go extinct, yet some drivers defy these predictions by persisting at low, stable frequencies for decades. One possible explanation for this discrepancy is that drivers are especially costly when homozygous, although empirical tests of this idea are rare and equivocal. Here, we measure the fitness of femaleDrosophila pseudoobscuracarrying zero, one or two copies of the X-linked driver sex ratio(SR).SRhad strong negative effects on female offspring production and the probability of reproductive failure, and these effects were largely similar across four genetic backgrounds.SRwas especially costly when homozygous. We used our fitness measurements to parametrize a population genetic model, and found that the female fitness costs observed here can explain the puzzlingly low allele frequency ofSRin nature. We also use the model to show how spatial variation in female mating behaviour, fitness costs ofSRand the reduced siring success ofSRmales can jointly explain the north–south cline inSRfrequencies across North America.
Characterization of the main steps in first shell formation in
Mytilus galloprovincialis
: possible role of tyrosinase
Authors: Miglioli A. , Dumollard R. , Balbi T. , Besnardeau L. , Canesi L.
Published: November 2019

Bivalve biomineralization is a highly complex and organized process, involving several molecular components identified in adults and larval stages. However, information is still scarce on the ontogeny of the organic matrix before calcification occurs. In this work, first shell formation was investigated in the mussel
Mytilus galloprovincialis
. The time course of organic matrix and CaCO
3
deposition were followed at close times post fertilization (24, 26, 29, 32, 48 h) by calcofluor and calcein staining, respectively. Both components showed an exponential trend in growth, with a delay between organic matrix and CaCO
3
deposition. mRNA levels of genes involved in matrix deposition (chitin synthase; tyrosinase- TYR) and calcification (carbonic anhydrase; extrapallial protein) were quantified by qPCR at 24 and 48 hours post fertilization (hpf) with respect to eggs. All transcripts were upregulated across early development, with TYR showing highest mRNA levels from 24 hpf. TYR transcripts were closely associated with matrix deposition as shown by
in situ
hybridization. The involvement of tyrosinase activity was supported by data obtained with the enzyme inhibitor N-phenylthiourea. Our results underline the pivotal role of shell matrix in driving first CaCO
3
deposition and the importance of tyrosinase in the formation of the first shell in
M. galloprovincialis
.
Earth's earliest and deepest purported fossils may be iron-mineralized chemical gardens
Authors: McMahon Sean
Published: November 2019

Recognizing fossil microorganisms is essential to the study of life's origin and evolution and to the ongoing search for life on Mars. Purported fossil microbes in ancient rocks include common assemblages of iron-mineral filaments and tubes. Recently, such assemblages have been interpreted to represent Earth's oldest body fossils, Earth's oldest fossil fungi, and Earth's best analogues for fossils that might form in the basaltic Martian subsurface. Many of these putative fossils exhibit hollow circular cross-sections, lifelike (non-crystallographic, constant-thickness, and bifurcate) branching, anastomosis, nestedness within ‘sheaths’, and other features interpreted as strong evidence for a biological origin, since no abiotic process consistent with the composition of the filaments has been shown to produce these specific lifelike features either in nature or in the laboratory. Here, I show experimentally that abiotic chemical gardening can mimic such purported fossils in both morphology and composition. In particular, chemical gardens meet morphological criteria previously proposed to establish biogenicity, while also producing the precursors to the iron minerals most commonly constitutive of filaments in the rock record. Chemical gardening is likely to occur in nature. Such microstructures should therefore not be assumed to represent fossil microbes without independent corroborating evidence.
Temperature-related biodiversity change across temperate marine and terrestrial systems
Authors: Antão Laura H. , Bates Amanda E. , Blowes Shane A. , Waldock Conor , Supp Sarah R. , Magurran Anne E. , Dornelas Maria , Schipper Aafke M.
Published: November 2019

Climate change is reshaping global biodiversity as species respond to changing temperatures. However, the net effects of climate-driven species redistribution on local assemblage diversity remain unknown. Here, we relate trends in species richness and abundance from 21,500 terrestrial and marine assemblage time series across temperate regions (23.5-60.0°) to changes in air or sea surface temperature. We find a strong coupling between biodiversity and temperature changes in the marine realm, which is conditional on the baseline climate. We detect increases in species richness with increasing temperature that is twice as pronounced in warmer locations, while abundance declines with warming in the warmest marine locations. In contrast, we did not detect systematic temperature-related richness or abundance trends on land, despite a greater magnitude of warming. We also found no evidence for an interaction between biodiversity change and latitude, further emphasizing the importance of baseline climate in structuring assemblages. As the world is committed to further warming, significant challenges remain in maintaining local biodiversity amongst the non-uniform inflow and outflow of “climate migrants” across distinct regions, especially in the ocean.
Much more than a clasp: Evolutionary pattern of amplexus diversity in anurans
Authors: Carvajal-Castro Juan D. , López-Aguirre Yelenny , Ospina-L Ana María , Santos Juan C. , Rojas Bibiana , Vargas-Salinas Fernando
Published: November 2019

The evolution and diversification of animal reproductive modes have been pivotal questions in behavioral ecology. Amphibians present the highest diversity of reproductive modes among vertebrates, involving various behavioral, physiological and morphological traits. One of such features is the amplexus, the clasp or embrace of males on females during reproduction, which is almost universal to anurans. Hypotheses about the origin amplexus are limited and have not been thoroughly tested, nor had they taken into account evolutionary relationships in most comparative studies. However, these considerations are crucial to understand the evolution of reproductive modes. Here, using an evolutionary framework, we reconstruct the ancestral state of amplexus in 686 anuran species; investigate whether the amplexus type is a conserved trait; and test whether sexual size dimorphism (SSD) could have influenced the amplexus type or male performance while clasping females. Overall, we found evidence of at least 35 evolutionary transitions in amplexus type across anurans. We also found that amplexus exhibits a high phylogenetic signal (it is conserved across Anura evolutionary history) and the amplexus type does not evolve in association with SSD. We discuss the implications of our findings on the diversity of amplexus types across anurans.
Optimal Mass Transport for Robust Texture Analysis
Authors: Belkhatir Zehor , Iyer Aditi , Mathews James C. , Pouryahya Maryam , Nadeem Saad , Deasy Joseph O. , Apte Aditya P. , Tannenbaum Allen R.
Published: November 2019

The emerging field of radiomics, which consists of transforming standard-of-care images to quantifiable scalar statistics, endeavors to reveal the information hidden in these macroscopic images. This field of research has found different applications ranging from phenotyping and tumor classification to outcome prediction and treatment planning. Texture analysis, which often consists of reducing spatial texture matrices to summary scalar features, has been shown to be important in many of the latter applications. However, as pointed out in many studies, some of the derived texture statistics are strongly correlated and tend to contribute redundant information; and are also sensitive to the parameters used in their computation, e.g., the number of gray intensity levels. In the present study, we propose first to consider texture matrices, with an emphasis on gray-level co-occurrence matrix (GLCM), as a non-parametric multivariate objects. The proposed modeling approach avoids evaluating redundant and strongly correlated features and also prevents the feature processing steps. Then, via the Wasserstein distance from optimal mass transport theory, we propose to compare these spatial objects to identify computerized tomography slices with dental artifacts in head and neck cancer. We demonstrate the robustness of the proposed classification approach with respect to the GLCM extraction parameters and the size of the training set. Comparisons with the random forest classifier, which is constructed on scalar texture features, demonstrates the efficiency and robustness of the proposed algorithm.
Low temperature transcriptionally modulates natural peel degreening in lemon (Citrus limon L.) fruit independently of endogenous ethylene
Authors: Mitalo Oscar W. , Otsuki Takumi , Okada Rui , Obitsu Saeka , Masuda Kanae , Hojo Yuko , Matsuura Takakazu , Mori Izumi C. , Abe Daigo , Asiche William O. , Akagi Takashi , Kubo Yasutaka , Ushijima Koichiro
Published: November 2019

Abstract

Peel degreening is an important aspect of fruit ripening in many citrus fruit, and earlier studies have shown that it can be advanced either by ethylene treatment or during low temperature storage. However, the important regulators and pathways involved in natural peel degreening remain largely unknown. To understand how natural peel degreening is regulated in lemon (Citrus limon L.) fruit, flavedo transcriptome and physiochemical changes in response to either ethylene treatment or low temperature were studied. Ethylene treatment induced rapid peel degreening which was strongly inhibited by the ethylene antagonist, 1-methylcyclopropene (1-MCP). Compared with 25°C, moderately low temperatures (5°C, 10°C, 15°C and 20°C) also triggered peel degreening. Surprisingly, repeated 1-MCP treatments failed to inhibit the peel degreening induced by low temperature. Transcriptome analysis revealed that low temperature and ethylene independently regulated genes associated with chlorophyll degradation, carotenoid metabolism, photosystem proteins, phytohormone biosynthesis and signalling, and transcription factors. On-tree peel degreening occurred along with environmental temperature drops, and it coincided with the differential expression of low temperature-regulated genes. In contrast, genes that were uniquely regulated by ethylene showed no significant expression changes during on-tree peel degreening. Based on these findings, we hypothesize that low temperature plays a prominent role in regulating natural peel degreening independently of ethylene in citrus fruit.

Highlight

Citrus peel degreening is promoted by low temperature via modulation of multiple genes associated with chlorophyll degradation, carotenoid biosynthesis, photosystem disassembly, phytohormones and transcription factors without involving ethylene signalling.
Mixture distributions in a stochastic gene expression model with delayed feedback
Authors: Bokes Pavol , Borri Alessandro , Palumbo Pasquale , Singh Abhyudai
Published: November 2019

Noise in gene expression can be substantively affected by the presence of production delay. Here we consider a mathematical model with bursty production of protein, a one-step production delay (the passage of which activates the protein), and feedback in the frequency of bursts. We specifically focus on examining the steady-state behaviour of the model in the slow-activation (i.e. large-delay) regime. Using a quasi-steady-state (QSS) approximation, we derive an autonomous ordinary differential equation for the inactive protein that applies in the slow-activation regime. If the differential equation is monostable, the steady-state distribution of the inactive (active) protein is approximated by a single Gaussian (Poisson) mode located at the globally stable steady state of the differential equation. If the differential equation is bistable (due to cooperative positive feedback), the steady-state distribution of the inactive (active) protein is approximated by a mixture of Gaussian (Poisson) modes located at the stable steady states; the weights of the modes are determined from a WKB approximation to the stationary distribution. The asymptotic results are compared to numerical solutions of the chemical master equation.
Extracellular electron transfer-dependent anaerobic oxidation of ammonium by anammox bacteria
Authors: Shaw Dario R. , Ali Muhammad , Katuri Krishna P. , Gralnick Jeffrey A. , Reimann Joachim , Mesman Rob , van Niftrik Laura , Jetten Mike S. M. , Saikaly Pascal E.
Published: November 2019

Anaerobic ammonium oxidation (anammox) by anammox bacteria contributes significantly to the global nitrogen cycle, and plays a major role in sustainable wastewater treatment. Anammox bacteria convert ammonium (NH4+) to dinitrogen gas (N2) using nitrite (NO2−) or nitric oxide (NO) as the electron acceptor. In the absence of NO2−or NO, anammox bacteria can couple formate oxidation to the reduction of metal oxides such as Fe(III) or Mn(IV). Their genomes contain homologs ofGeobacterandShewanellacytochromesinvolved in extracellularelectron transfer (EET). However, it is still unknown whether anammox bacteria have EET capability and can couple the oxidation of NH4+with transfer of electrons to carbon-based insoluble extracellular electron acceptors. Here we show using complementary approaches that in the absence of NO2−, freshwater and marine anammox bacteria couple the oxidation of NH4+with transfer of electrons to carbon-based insoluble extracellular electron acceptors such as graphene oxide (GO) or electrodes poised at a certain potential in microbial electrolysis cells (MECs). Metagenomics, fluorescencein-situhybridization and electrochemical analyses coupled with MEC performance confirmed that anammox electrode biofilms were responsible for current generation through EET-dependent oxidation of NH4+.15N-labelling experiments revealed the molecular mechanism of the EET-dependent anammox process. NH4+was oxidized to N2via hydroxylamine (NH2OH) as intermediate when electrode was the terminal electron acceptor. Comparative transcriptomics analysis supported isotope labelling experiments and revealed an alternative pathway for NH4+oxidation coupled to EET when electrode is used as electron acceptor compared to NO2−as electron acceptor. To our knowledge, our results provide the first experimental evidence that marine and freshwater anammox bacteria can couple NH4+oxidation with EET, which is a significant finding, and challenges our perception of a key player of anaerobic oxidation of NH4+in natural environments and engineered systems.
Mitochondrial substitution rates estimation for molecular clock analyses in modern birds based on full mitochondrial genomes
Authors: Arcones Angel , Ponti Raquel , Vieites David R.
Published: November 2019

Abstractti

Mitochondrial DNA (mtDNA) is a very popular resource in the study of evolutionary processes in birds, and especially to infer divergence times between lineages. These inferences rely on rates of substitution in the mtDNA genes that, ideally, are specific for the studied taxa. But as such values are often unavailable many studies fixed rate values generalised from other studies, such as the popular “standard molecular clock”. However the validity of these universal rates across all bird lineages and for the different mtDNA has been severely questioned. Thus, we here performed the most comprehensive calibration of the mtDNA molecular clock in birds, with the inclusion of complete mitochondrial genomes for 622 bird species and 25 reliable fossil calibrations. The results show variation in the rates between lineages and especially between markers, contradicting the universality of the standard clock. Moreover, we provide especific rates for every mtDNA marker (except D-loop) in each of the sampled avian orders, which should help improve future estimations of divergence times between bird species or populations.
Mechano-calcium and mechano-electric feedbacks in the human cardiomyocyte analyzed in a mathematical model
Authors: Balakina-Vikulova Nathalie A. , Panfilov Alexander , Solovyova Olga , Katsnelson Leonid B.
Published: November 2019

Experiments on animal hearts (rat, rabbit, guinea pig, etc.) have demonstrated that mechano-calcium feedback (MCF) and mechano-electric feedback (MEF) are very important for myocardial self-regulation because they adjust the cardiomyocyte contractile function to various mechanical loads and to mechanical interactions between heterogeneous myocardial segments in the ventricle walls. Inin vitroexperiments on these animals, MCF and MEF manifested themselves in several basic classical phenomena (e.g. load dependence, length dependence of isometric twitches, etc.), and in the respective responses of calcium transients and action potentials. However, it is extremely difficult to study simultaneously the electrical, calcium, and mechanical activities of the human heart musclein vitro. Mathematical modeling is a useful tool for exploring these phenomena. We have developed a novel model to describe electromechanical coupling and mechano-electric feedbacks in the human cardiomyocyte. It combines the ‘ten Tusscher – Panfilov’ electrophysiological model of the human cardiomyocyte with our module of myocardium mechanical activity taken from the ‘Ekaterinburg – Oxford’ model and adjusted to human data. Using it, we simulated isometric and afterloaded twitches and effects of MCF and MEF on excitation-contraction coupling. MCF and MEF were found to affect significantly the duration of the calcium transient and action potential in the human cardiomyocyte model in response to both smaller afterloads as compared to bigger ones and various mechanical interventions applied during isometric and afterloaded twitches.
Multiplexing rhythmic information by spike timing dependent plasticity
Authors: Sherf Nimrod , Shamir Maoz
Published: November 2019

Rhythmic activity has been associated with a wide range of cognitive processes including the encoding of sensory information, navigation, the transfer of emotional information and others. Previous studies have shown that spike-timing-dependent plasticity (STDP) can facilitate the transfer of rhythmic activity downstream the information processing pathway. However, STDP has also been known to generate strong winner-take-all like competitions between subgroups of correlated synaptic inputs. Consequently, one might expect that STDP would induce strong competition between different rhythmicity channels thus preventing the multiplexing of information across different frequency channels. This study explored whether STDP facilitates the multiplexing of information across multiple frequency channels, and if so, under what conditions. We investigated the STDP dynamics in the framework of a model consisting of two competing sub-populations of neurons that synapse in a feedforward manner onto a single post-synaptic neuron. Each sub-population was assumed to oscillate in an independent manner and in a different frequency band. To investigate the STDP dynamics, a mean field Fokker-Planck theory was developed in the limit of the slow learning rate. Surprisingly, our theory predicted limited interactions between the different sub-groups. Our analysis further revealed that the interaction between these channels was mainly mediated by the shared component of the mean activity. Next, we generalized these results beyond the simplistic model using numerical simulations. We found that for a wide range of parameters, the system converged to a solution in which the post-synaptic neuron responded to both rhythms. Nevertheless, all the synaptic weights remained dynamic and did not converge to a fixed point. These findings imply that STDP can support the multiplexing of rhythmic information, and demonstrate how functionality (multiplexing of information) can be retained in the face of continuous remodeling of all the synaptic weights.
Intravenous indocyanine green dye is insufficient for robust immune cell labelling in the human retina
Authors: Bell Oliver H. , Carreño Ester , Williams Emily L. , Wu Jiahui , Copland David A. , Bora Monalisa , Kobayter Lina , Fruttiger Marcus , Sim Dawn A. , Lee Richard W.J. , Dick Andrew D. , Chu Colin J.
Published: November 2019

It is not currently possible to reliably visualise and track immune cells in the human central nervous system or eye. Previous work demonstrated that indocyanine green (ICG) dye could label immune cells and be imaged after a delay during disease in the mouse retina. We report a pilot study investigating if ICG can similarly label immune cells within the human retina. Twelve adult participants receiving ICG angiography as part of routine standard of care were recruited. Baseline retinal images were obtained prior to ICG administration then repeated over a period ranging from 2 hours to 9 days. Matched peripheral blood samples, in addition to human and mouse macrophage cultures as controls, were analysed by flow cytometry. Differences between the delayed near infrared ICG imaging and 488 nm autofluorescence was observed across pathologies, likely arising from the retinal pigment epithelium (RPE). Only one subject demonstrated ICG signal on peripheral blood myeloid cells and only three distinct cell-sized signals appeared over time within the retina of three participants. No significant increase in immune cell activation markers were detected after ICG administration. ICG accumulated in the endosomes of macrophage cultures and was detectable above a minimum concentration, suggesting cell labelling is possible. ICG can label RPE and may be used as an additional biomarker for cell health across a range of retinal disorders. Standard clinical doses of intravenous ICG do not lead to robust immune cell labelling in human blood or retina and further optimisation in dose and route are required.
Insulin signal transduction is impaired in the type 2 diabetic retina
Authors: Jiang Youde , Liu Li , Li Hainan , Wang Jie-Mei , Steinle Jena J.
Published: November 2019

Rates of type 2 diabetes are reaching epidemic levels. Yet, the tissue specific alterations due to insulin resistance are only recently being investigated. The goal of the present study was to evaluate retinal insulin signal transduction in a common mouse model of type 2 diabetes, the db/db mouse. Retinal lysates from five month old male db/db and db/+ (control) mice were collected and processed for Western blotting or ELISA analyses for insulin receptor, insulin receptor substrate-1 (IRS-1), Akt, tumor necrosis factor alpha (TNFα) and caspase 3 levels. Data demonstrate increased TNFα and IRS-1 phosphorylation on serine 307. This led to decreased Akt phosphorylation on serine 473 and increased cleavage of caspase 3. Taken together, the data suggest dysfunctional insulin signaling in the retina of the db/db mouse.
A field experiment to assess passage of juvenile salmonids across beaver dams during low flow conditions in a tributary to the Klamath River, California, USA
Authors: Pollock Michael Moritz , Witmore Shari , Yokel Erich
Published: November 2019

Across Eurasia and North America, beaver (Castorspp), their dams and their human-built analogues are becoming increasingly common restoration tools to facilitate recovery of streams and wetlands, providing a natural and cost-effective means of restoring dynamic fluvial ecosystems. Although the use of beaver ponds by numerous fish and wildlife species is well documented, debate continues as to the benefits of beaver dams, primarily because dams are perceived as barriers to the movement of fishes, particularly migratory species such as salmonids. In this study, through a series of field experiments, we tested the ability of juvenile salmonids to cross constructed beaver dams (aka beaver dam analogues). Two species, coho salmon (Oncorhynchus kisutch) and steelhead trout (O. mykiss), were tracked using passive integrated transponder tags (PIT tags) as they crossed constructed beaver dams. We found that when we tagged and moved late-summer parr from immediately upstream of the dams to immediately downstream of them, most of them were detected upstream within 36 hours of displacement. By the end of a 21-day field experiment, 91% of the displaced juvenile coho and 54% of the juvenile steelhead trout were detected on antennas upstream of the dams while <1% of the coho and 15% of the steelhead trout were detected on antennas in the release pool below the dams. A similar but shorter 4-day pilot experiment with only steelhead trout produced similar results. In contrast, in a non-displacement experiment, juveniles of both species that were captured, tagged and released in a pool 50 m below the dams showed little inclination to move upstream. Finally by measuring hydraulic conditions at the major flowpaths over and around the dams, we provide insight into conditions under which juvenile salmonids are able to cross these constructed beaver dams, which should help guide future restoration efforts.
An Escherichia coli Chassis for Production of Electrically Conductive Protein Nanowires
Authors: Ueki Toshiyuki , Walker David J.F. , Woodard Trevor L. , Nevin Kelly P. , Nonnenmann Stephen S. , Lovley Derek R.
Published: November 2019

Geobacter sulfurreducens’ pilin-based electrically conductive protein nanowires (e-PNs) are a revolutionary electronic material. They offer novel options for electronic sensing applications and have the remarkable ability to harvest electrical energy from atmospheric humidity. However, technical constraints limit mass cultivation and genetic manipulation of G. sulfurreducens. Therefore, we designed a strain of Escherichia coli to express e-PNs by introducing a plasmid that contained an inducible operon with E. coli genes for type IV pili biogenesis machinery and a synthetic gene designed to yield a peptide monomer that could be assembled into e-PNs. The e-PNs expressed in E. coli, and harvested with a simple filtration method, had the same diameter (3 nm) and conductance as e-PNs expressed in G. sulfurreducens. These results, coupled with the robustness of E. coli for mass cultivation and the extensive E. coli toolbox for genetic manipulation, greatly expands opportunities for large-scale fabrication of novel e-PNs.
ACTOR: a latent Dirichlet model to compare expressed isoform proportions to a reference panel
Authors: McCabe Sean D. , Nobel Andrew B. , Love Michael I.
Published: November 2019

The relative proportion of RNA isoforms expressed for a given gene has been associated with disease states in cancer, retinal diseases, and neurological disorders. Examination of relative isoform proportions can help determine biological mechanisms, but such analyses often require a per-gene investigation of splicing patterns. Leveraging large public datasets produced by genomic consortia as a reference, one can compare splicing patterns in a dataset of interest with those of a reference panel in which samples are divided into distinct groups (tissue of origin, disease status, etc). We propose ACTOR, a latent Dirichlet model with Dirichlet Multinomial observations to compare expressed isoform proportions in a dataset to an independent reference panel. We use a variational Bayes procedure to estimate posterior distributions for the group membership of one or more samples. Using the Genotype-Tissue Expression (GTEx) project as a reference dataset, we evaluate ACTOR on simulated and real RNA-seq datasets to determine tissue-type classifications of genes. ACTOR is publicly available as an R package at https://github.com/mccabes292/actor.
Combining hypoxia-activated prodrugs and radiotherapy in silico: Impact of treatment scheduling and the intra-tumoural oxygen landscape
Authors: Hamis Sara , Kohandel Mohammad , Dubois Ludwig J , Yaromina Ala , Lambin Philippe , Powathil Gibin G
Published: November 2019

Hypoxia-activated prodrugs (HAPs) present a conceptually elegant approach to not only overcome, but better yet, exploit intra-tumoural hypoxia. Despite being successful in vitro and in vivo, HAPs are yet to achieve successful results in clinical settings. It has been hypothesised that this lack of clinical success can, in part, be explained by the insufficiently stringent clinical screening selection of determining which tumours are suitable for HAP treatments.

Taking a mathematical modelling approach, we investigate how tumour properties and HAP-radiation scheduling influence treatment outcomes in simulated tumours. The following key results are demonstrated in silico: (i) HAP and ionising radiation (IR) monotherapies may attack tumours in dissimilar, and complementary, ways. (ii) HAP-IR scheduling may impact treatment efficacy. (iii) HAPs may function as IR treatment intensifiers. (iv) The spatio-temporal intra-tumoural oxygen landscape may impact HAP efficacy. Our in silico framework is based on an on-lattice, hybrid, multiscale cellular automaton spanning three spatial dimensions. The mathematical model for tumour spheroid growth is parameterised by multicellular tumour spheroid (MCTS) data.

Author Summary

When cancer patients present with solid tumours, the tumours often contain regions that are oxygen-deprived or, in other words, hypoxic. Hypoxic cancer cells are more resistant to conventional anti-cancer therapies, such as chemotherapy and radiotherapy, and therefore tumour hypoxia may complicate treatments. Hypoxia-activated prodrugs constitute a conceptually elegant approach to not only overcome, but better yet, exploit tumour hypoxia. Hypoxia-activated prodrugs are drugs that act as Trojan horses, they are theoretically harmless vehicles that are converted into warheads when they reach their targets: hypoxic tumour cells. Despite being conceptually clever and successful in experimental settings, hypoxia-activated prodrugs are yet to achieve successful results in clinical trials. It has been hypothesised that this lack of clinical success can, in part, be explained by an insufficiently stringent clinical screening selection of determining which tumours are suitable for hypoxia-activated prodrug treatments.

In this article, we investigate how simulated tumours with different oxygen landscapes respond to anti-cancer treatments that include hypoxia-activated prodrugs, either alone or in combination with radiotherapy. Our simulation framework is based on a mathematical model that describes how individual cancer cells in a tumour divide and respond to treatments. We demonstrate that the efficacy of hypoxia-activated prodrugs depends on both the treatment scheduling, and on the oxygen landscape of the specific, simulated tumour.
Quantitative Delineation of Herpesviruses in Bats for use in Ecological Studies
Authors: Sjodin Anna R. , Willig Michael R. , Anthony Simon J.
Published: November 2019

Public health concerns about recent viral epidemics have motivated researchers to seek transdisciplinary understanding of infection in wildlife hosts. With its deep history devoted to explaining the abundance and distribution of organisms, ecology can augment current methods for studying viral dynamics. However, datasets allowing ecological explorations of viral communities are lacking, and common methods for delineating viral operational taxonomic units (OTUs), or “species”, are subjective. Here, we comprehensively sampled 1,086 bats from two Puerto Rican caves and tested them for infection with herpesviruses. Using percent identity of nucleotides and a machine learning algorithm, we categorized herpesviruses into 41 OTUs, representing approximately 80% of all herpesviruses in the host community. Although 13 OTUs were detected in multiple host species, OTUs generally exhibited host specificity by infecting a core host species at a significantly higher prevalence than in all other species combined. Only two OTUs showed significantly different prevalence between host sexes. This work is the first exploration of viral community ecology in a community of wildlife hosts.
RepeatModeler2: automated genomic discovery of transposable element families
Authors: Flynn Jullien M. , Hubley Robert , Goubert Clément , Rosen Jeb , Clark Andrew G. , Feschotte Cédric , Smit Arian F.
Published: November 2019

The accelerating pace of genome sequencing throughout the tree of life is driving the need for improved unsupervised annotation of genome components such as transposable elements (TEs). Because the types and sequences of TEs are highly variable across species, automated TE discovery and annotation are challenging and time-consuming tasks. A critical first step is the de novo identification and accurate compilation of sequence models representing all the unique TE families dispersed in the genome. Here we introduce RepeatModeler2, a new pipeline that greatly facilitates this process. This new program brings substantial improvements over the original version of RepeatModeler, one of the most widely used tools for TE discovery. In particular, this version incorporates a module for structural discovery of complete LTR retroelements, which are widespread in eukaryotic genomes but recalcitrant to automated identification because of their size and sequence complexity. We benchmarked RepeatModeler2 on three model species with diverse TE landscapes and high-quality, manually curated TE libraries:Drosophila melanogaster(fruit fly),Danio rerio(zebrafish), andOryza sativa(rice). In these three species, RepeatModeler2 identified approximately three times more consensus sequences matching with >95% sequence identity and sequence coverage to the manually curated sequences than the original RepeatModeler. As expected, the greatest improvement is for LTR retroelements. The program had an extremely low false positive rate when applied to simulated genomes devoid of TEs. Thus, RepeatModeler2 represents a valuable addition to the genome annotation toolkit that will enhance the identification and study of TEs in eukaryotic genome sequences. RepeatModeler2 is available as source code or a containerized package under an open license (https://github.com/Dfam-consortium/RepeatModeler,https://github.com/Dfam-consortium/TETools).

Significance

Genome sequences are being produced for more and more eukaryotic species. The bulk of these genomes is composed of parasitic, self-mobilizing transposable elements (TEs) that play important roles in organismal evolution. Thus there is a pressing need for developing software that can accurately identify the diverse set of TEs dispersed in genome sequences. Here we introduce RepeatModeler2, an easy-to-use package for the curation of reference TE libraries which can be applied to any eukaryotic species. Through several major improvements over the previous version, RepeatModeler2 is able to produce libraries that recapitulate the known composition of three model species with some of the most complex TE landscapes. Thus RepeatModeler2 will greatly enhance the discovery and annotation of TEs in genome sequences.
Chronic cortisol exposure in early development leads to neuroendocrine dysregulation in adulthood
Authors: Hartig Ellen I. , Zhu Shusen , King Benjamin L. , Coffman James A.
Published: November 2019

Objective

Chronic early life stress can affect development of the neuroendocrine stress system, leading to its persistent dysregulation and consequently increased disease risk in adulthood. One contributing factor is thought to be epigenetic programming in response to chronic cortisol exposure during early development. We have previously shown that zebrafish embryos treated chronically with cortisol develop into adults with constitutively elevated whole body cortisol and aberrant immune gene expression. The objective of the experiments reported here was to further characterize the phenotype of those adults.

Results

We find that adult zebrafish derived from cortisol-treated embryos have aberrant cortisol levels, tissue distribution, and dynamics, which correlate with differential activity of key glucocorticoid-responsive regulatory genes klf9 and fkbp5 in blood and brain.
Leopard: fast decoding cell type-specific transcription factor binding landscape at single-nucleotide resolution
Authors: Li Hongyang , Guan Yuanfang
Published: November 2019

Decoding the cell type-specific transcription factor (TF) binding landscape at single-nucleotide resolution is crucial for understanding the regulatory mechanisms underlying many fundamental biological processes and human diseases. However, limits on time and resources restrict the high-resolution experimental measurements of TF binding profiles of all possible TF-cell type combinations. Previous computational approaches either can not distinguish the cell-context-dependent TF binding profiles across diverse cell types, or only provide a relatively low-resolution prediction. Here we present a novel deep learning approach, Leopard, for predicting TF-binding sites at single-nucleotide resolution, achieving the median area under receiver operating characteristic curve (AUROC) of 0.994. Our method substantially outperformed state-of-the-art methods Anchor and FactorNet, improving the performance by 19% and 27% respectively despite evaluated at a lower resolution. Meanwhile, by leveraging a many-to-many neural network architecture, Leopard features hundred-fold to thousand-fold speedup compared to current many-to-one machine learning methods.
ALTERED MERISTEM PROGRAM1regulates leaf identity independent of miR156-mediated translational repression
Authors: Fouracre Jim P. , Chen Victoria J. , Poethig R. Scott
Published: November 2019

InArabidopsis, loss of the carboxypeptidase, ALTERED MERISTEM PROGRAM1 (AMP1), produces an increase in the rate of leaf initiation, an enlarged shoot apical meristem and an increase in the number of juvenile leaves. This phenotype is also observed in plants with reduced levels of miR156-targetedSQUAMOSA PROMOTER BINDING PROTEIN-LIKE(SPL) transcription factors, suggesting that AMP1 may promote SPL activity. However, we found that theamp1phenotype is only partially corrected by elevatedSPLgene expression, and thatamp1has no significant effect onSPLtranscript levels, or on the level or the activity of miR156. Although evidence from a previous study suggests that AMP1 promotes miRNA-mediated translational repression,amp1did not prevent the translational repression of the miR156 target,SPL9, or the miR159 target,MYB33.These results suggest thatAMP1regulates vegetative phase change downstream of, or in parallel to, the miR156/SPLpathway and that it is not universally required for miRNA-mediated translational repression.

Summary statement

We show that loss of the carboxypeptidase, AMP1, does not interfere with the function of miR156 or miR159, suggesting that AMP1 is not universally required for miRNA-mediated translational repression inArabidopsis.
Structural characterization of an intermediate reveals a unified mechanism for the CLC Cl−/H+ transport cycle
Authors: Chavan Tanmay S. , Cheng Ricky C. , Jiang Tao , Mathews Irimpan I. , Stein Richard A. , Koehl Antoine , Mchaourab Hassane S. , Tajkhorshid Emad , Maduke Merritt
Published: November 2019

Among coupled exchangers, CLCs uniquely catalyze the exchange of oppositely charged ions (Cl− for H+). Transport-cycle models to describe and explain this unusual mechanism have been proposed based on known CLC structures. While the proposed models harmonize many experimental findings, there have remained gaps and inconsistencies in our understanding. One limitation has been that global conformational change – which occurs in all conventional transporter mechanisms – has not been observed in any high-resolution structure. Here, we describe the 2.6 Å structure of a CLC mutant designed to mimic the fully H+-loaded transporter. This structure reveals a global conformational change to a state that has improved accessibility for the Cl− substrate from the extracellular side and new conformations for two key glutamate residues. Based on this new structure, together with DEER measurements, MD simulations, and functional studies, we propose a unified model of the CLC transport mechanism that reconciles existing data on all CLC-type proteins.