bluuebunny/crossref_metadata_2025 huggingface dataset:
The heritability of chimpanzee and human brain asymmetry
Authors: Gómez-Robles Aida , Hopkins William D. , Schapiro Steven J. , Sherwood Chet C.
Published: December 2016

Human brains are markedly asymmetric in structure and lateralized in function, which suggests a relationship between these two properties. The brains of other closely related primates, such as chimpanzees, show similar patterns of asymmetry, but to a lesser degree, indicating an increase in anatomical and functional asymmetry during hominin evolution. We analysed the heritability of cerebral asymmetry in chimpanzees and humans using classic morphometrics, geometric morphometrics, and quantitative genetic techniques. In our analyses, we separated directional asymmetry and fluctuating asymmetry (FA), which is indicative of environmental influences during development. We show that directional patterns of asymmetry, those that are consistently present in most individuals in a population, do not have significant heritability when measured through simple linear metrics, but they have marginally significant heritability in humans when assessed through three-dimensional configurations of landmarks that reflect variation in the size, position, and orientation of different cortical regions with respect to each other. Furthermore, genetic correlations between left and right hemispheres are substantially lower in humans than in chimpanzees, which points to a relatively stronger environmental influence on left–right differences in humans. We also show that the level of FA has significant heritability in both species in some regions of the cerebral cortex. This suggests that brain responsiveness to environmental influences, which may reflect neural plasticity, has genetic bases in both species. These results have implications for the evolvability of brain asymmetry and plasticity among humans and our close relatives.
Transcriptional regulation of a horizontally transferred gene from bacterium to chordate
Authors: Sasakura Yasunori , Ogura Yosuke , Treen Nicholas , Yokomori Rui , Park Sung-Joon , Nakai Kenta , Saiga Hidetoshi , Sakuma Tetsushi , Yamamoto Takashi , Fujiwara Shigeki , Yoshida Keita
Published: December 2016

The horizontal transfer of genes between distantly related organisms is undoubtedly a major factor in the evolution of novel traits. Because genes are functionless without expression, horizontally transferred genes must acquire appropriate transcriptional regulations in their recipient organisms, although the evolutionary mechanism is not known well. The defining characteristic of tunicates is the presence of a cellulose containing tunic covering the adult and larval body surface. Cellulose synthase was acquired by horizontal gene transfer from Actinobacteria. We found that acquisition of the binding site of AP-2 transcription factor was essential for tunicate cellulose synthase to gain epidermal-specific expression. Actinobacteria have very GC-rich genomes, regions of which are capable of inducing specific expression in the tunicate epidermis as the AP-2 binds to a GC-rich region. Therefore, the actinobacterial cellulose synthase could have been potentiated to evolve its new function in the ancestor of tunicates with a higher probability than the evolution depending solely on a spontaneous event.
The costs of a big brain: extreme encephalization results in higher energetic demand and reduced hypoxia tolerance in weakly electric African fishes
Authors: Sukhum Kimberley V. , Freiler Megan K. , Wang Robert , Carlson Bruce A.
Published: December 2016

A large brain can offer several cognitive advantages. However, brain tissue has an especially high metabolic rate. Thus, evolving an enlarged brain requires either a decrease in other energetic requirements, or an increase in overall energy consumption. Previous studies have found conflicting evidence for these hypotheses, leaving the metabolic costs and constraints in the evolution of increased encephalization unclear. Mormyrid electric fishes have extreme encephalization comparable to that of primates. Here, we show that brain size varies widely among mormyrid species, and that there is little evidence for a trade-off with organ size, but instead a correlation between brain size and resting oxygen consumption rate. Additionally, we show that increased brain size correlates with decreased hypoxia tolerance. Our data thus provide a non-mammalian example of extreme encephalization that is accommodated by an increase in overall energy consumption. Previous studies have found energetic trade-offs with variation in brain size in taxa that have not experienced extreme encephalization comparable with that of primates and mormyrids. Therefore, we suggest that energetic trade-offs can only explain the evolution of moderate increases in brain size, and that the energetic requirements of extreme encephalization may necessitate increased overall energy investment.
Antibody responses to avian influenza viruses in wild birds broaden with age
Authors: Hill Sarah C. , Manvell Ruth J. , Schulenburg Bodo , Shell Wendy , Wikramaratna Paul S. , Perrins Christopher , Sheldon Ben C. , Brown Ian H. , Pybus Oliver G.
Published: December 2016

For viruses such as avian influenza, immunity within a host population can drive the emergence of new strains by selecting for viruses with novel antigens that avoid immune recognition. The accumulation of acquired immunity with age is hypothesized to affect how influenza viruses emerge and spread in species of different lifespans. Despite its importance for understanding the behaviour of avian influenza viruses, little is known about age-related accumulation of immunity in the virus's primary reservoir, wild birds. To address this, we studied the age structure of immune responses to avian influenza virus in a wild swan population (
Cygnus olor
), before and after the population experienced an outbreak of highly pathogenic H5N1 avian influenza in 2008. We performed haemagglutination inhibition assays on sampled sera for five avian influenza strains and show that breadth of response accumulates with age. The observed age-related distribution of antibody responses to avian influenza strains may explain the age-dependent mortality observed during the highly pathogenic H5N1 outbreak. Age structures and species lifespan are probably important determinants of viral epidemiology and virulence in birds.
Urbanization drives the evolution of parallel clines in plant populations
Authors: Thompson Ken A. , Renaudin Marie , Johnson Marc T. J.
Published: December 2016

Urban ecosystems are an increasingly dominant feature of terrestrial landscapes. While evidence that species can adapt to urban environments is accumulating, the mechanisms through which urbanization imposes natural selection on populations are poorly understood. The identification of adaptive phenotypic changes (i.e. clines) along urbanization gradients would facilitate our understanding of the selective factors driving adaptation in cities. Here, we test for phenotypic clines in urban ecosystems by sampling the frequency of a Mendelian-inherited trait—cyanogenesis—in white clover (
Trifolium repens
L.) populations along urbanization gradients in four cities. Cyanogenesis protects plants from herbivores, but reduces tolerance to freezing temperatures. We found that the frequency of cyanogenic plants within populations decreased towards the urban centre in three of four cities. A field experiment indicated that spatial variation in herbivory is unlikely to explain these clines. Rather, colder minimum winter ground temperatures in urban areas compared with non-urban areas, caused by reduced snow cover in cities, may select against cyanogenesis. In the city with no cline, high snow cover might protect plants from freezing damage in the city centre. Our study suggests that populations are adapting to urbanization gradients, but regional climatic patterns may ultimately determine whether adaptation occurs.
Faithful or not: direct and indirect effects of climate on extra-pair paternities in a population of Alpine marmots
Authors: Bichet Coraline , Allainé Dominique , Sauzet Sandrine , Cohas Aurélie
Published: December 2016

Despite being identified an area that is poorly understood regarding the effects of climate change, behavioural responses to climatic variability are seldom explored. Climatic variability is likely to cause large inter-annual variation in the frequency of extra-pair litters produced, a widespread alternative mating tactic to help prevent, correct or minimize the negative consequences of sub-optimal mate choice. In this study, we investigated how climatic variability affects the inter-annual variation in the proportion of extra-pair litters in a wild population of Alpine marmots. During 22 years of monitoring, the annual proportion of extra-pair litters directly increased with the onset of earlier springs and indirectly with increased snow in winters. Snowier winters resulted in a higher proportion of families with sexually mature male subordinates and thus, created a social context within which extra-pair paternity was favoured. Earlier spring snowmelt could create this pattern by relaxing energetic, movement and time constraints. Further, deeper snow in winter could also contribute by increasing litter size and juvenile survival. Optimal mate choice is particularly relevant to generate adaptive genetic diversity. Understanding the influence of environmental conditions and the capacity of the individuals to cope with them is crucial within the context of rapid climate change.
Size evolution in microorganisms masks trade-offs predicted by the growth rate hypothesis
Authors: Gounand Isabelle , Daufresne Tanguy , Gravel Dominique , Bouvier Corinne , Bouvier Thierry , Combe Marine , Gougat-Barbera Claire , Poly Franck , Torres-Barceló Clara , Mouquet Nicolas
Published: December 2016

Adaptation to local resource availability depends on responses in growth rate and nutrient acquisition. The growth rate hypothesis (GRH) suggests that growing fast should impair competitive abilities for phosphorus and nitrogen due to high demand for biosynthesis. However, in microorganisms, size influences both growth and uptake rates, which may mask trade-offs and instead generate a positive relationship between these traits (size hypothesis, SH). Here, we evolved a gradient of maximum growth rate (μmax) from a single bacterium ancestor to test the relationship amongμmax, competitive ability for nutrients and cell size, while controlling for evolutionary history. We found a strong positive correlation betweenμmaxand competitive ability for phosphorus, associated with a trade-off betweenμmaxand cell size: strains selected for highμmaxwere smaller and better competitors for phosphorus. Our results strongly support the SH, while the trade-offs expected under GRH were not apparent. Beyond plasticity, unicellular populations can respond rapidly to selection pressure through joint evolution of their size and maximum growth rate. Our study stresses that physiological links between these traits tightly shape the evolution of competitive strategies.
Modulation of recognition memory performance by light requires both melanopsin and classical photoreceptors
Authors: Tam Shu K. E. , Hasan Sibah , Hughes Steven , Hankins Mark W. , Foster Russell G. , Bannerman David M. , Peirson Stuart N.
Published: December 2016

Acute light exposure exerts various effects on physiology and behaviour. Although the effects of light on brain network activity in humans are well demonstrated, the effects of light on cognitive performance are inconclusive, with the size, as well as direction, of the effect depending on the nature of the task. Similarly, in nocturnal rodents, bright light can either facilitate or disrupt performance depending on the type of task employed. Crucially, it is unclear whether the effects of light on behavioural performance are mediated via the classical image-forming rods and cones or the melanopsin-expressing photosensitive retinal ganglion cells. Here, we investigate the modulatory effects of light on memory performance in mice using the spontaneous object recognition task. Importantly, we examine which photoreceptors are required to mediate the effects of light on memory performance. By using a cross-over design, we show that object recognition memory is disrupted when the test phase is conducted under a bright light (350 lux), regardless of the light level in the sample phase (10 or 350 lux), demonstrating that exposure to a bright light at the time of test, rather than at the time of encoding, impairs performance. Strikingly, the modulatory effect of light on memory performance is completely abolished in both melanopsin-deficient and rodless–coneless mice. Our findings provide direct evidence that melanopsin-driven and rod/cone-driven photoresponses are integrated in order to mediate the effect of light on memory performance.
Controlled fluorescence in a beetle's photonic structure and its sensitivity to environmentally induced changes
Authors: Mouchet Sébastien R. , Lobet Michaël , Kolaric Branko , Kaczmarek Anna M. , Van Deun Rik , Vukusic Peter , Deparis Olivier , Van Hooijdonk Eloise
Published: December 2016

The scales covering the elytra of the male
Hoplia coerulea
beetle contain fluorophores embedded within a porous photonic structure. The photonic structure controls both insect colour (reflected light) and fluorescence emission. Herein, the effects of water-induced changes on the fluorescence emission from the beetle were investigated. The fluorescence emission peak wavelength was observed to blue-shift on water immersion of the elytra whereas its reflectance peak wavelength was observed to red-shift. Time-resolved fluorescence measurements, together with optical simulations, confirmed that the radiative emission is controlled by a naturally engineered photonic bandgap while the elytra are in the dry state, whereas non-radiative relaxation pathways dominate the emission response of wet elytra.
Partitioning prediction uncertainty in climate-dependent population models
Authors: Gauthier Gilles , Péron Guillaume , Lebreton Jean-Dominique , Grenier Patrick , van Oudenhove Louise
Published: December 2016

The science of complex systems is increasingly asked to forecast the consequences of climate change. As a result, scientists are now engaged in making predictions about an uncertain future, which entails the efficient communication of this uncertainty. Here we show the benefits of hierarchically decomposing the uncertainty in predicted changes in animal population size into its components due to structural uncertainty in climate scenarios (greenhouse gas emissions and global circulation models), structural uncertainty in the demographic model, climatic stochasticity, environmental stochasticity unexplained by climate–demographic trait relationships, and sampling variance in demographic parameter estimates. We quantify components of uncertainty surrounding the future abundance of a migratory bird, the greater snow goose (
Chen caeruslescens atlantica
), using a process-based demographic model covering their full annual cycle. Our model predicts a slow population increase but with a large prediction uncertainty. As expected from theoretical variance decomposition rules, the contribution of sampling variance to prediction uncertainty rapidly overcomes that of process variance and dominates. Among the sources of process variance, uncertainty in the climate scenarios contributed less than 3% of the total prediction variance over a 40-year period, much less than environmental stochasticity. Our study exemplifies opportunities to improve the forecasting of complex systems using long-term studies and the challenges inherent to predicting the future of stochastic systems.
Direct transfer of learned behaviour via cell fusion in non-neural organisms
Authors: Vogel David , Dussutour Audrey
Published: December 2016

Cell fusion is a fundamental phenomenon observed in all eukaryotes. Cells can exchange resources such as molecules or organelles during fusion. In this paper, we ask whether a cell can also transfer an adaptive response to a fusion partner. We addressed this question in the unicellular slime mould
Physarum polycephalum
, in which cell–cell fusion is extremely common. Slime moulds are capable of habituation, a simple form of learning, when repeatedly exposed to an innocuous repellent, despite lacking neurons and comprising only a single cell. In this paper, we present a set of experiments demonstrating that slime moulds habituated to a repellent can transfer this adaptive response by cell fusion to individuals that have never encountered the repellent. In addition, we show that a slime mould resulting from the fusion of a minority of habituated slime moulds and a majority of unhabituated ones still shows an adaptive response to the repellent. Finally, we further reveal that fusion must last a certain time to ensure an effective transfer of the behavioural adaptation between slime moulds. Our results provide strong experimental evidence that slime moulds exhibit transfer of learned behaviour during cell fusion and raise the possibility that similar phenomena may occur in other cell–cell fusion systems.
Transcranial stimulation enhances memory-relevant sleep oscillations and their functional coupling in mild cognitive impairment
Authors: Ladenbauer Julia , Ladenbauer Josef , Külzow Nadine , de Boor Rebecca , Avramova Elena , Grittner Ulrike , Flöel Agnes
Published: December 2016

Alzheimer’s disease (AD) not only involves loss of memory functions but also prominent deterioration of sleep physiology, already evident in the stage ofmild cognitive impairment(MCI). Cortical slow oscillations (SO, 0.5-1 Hz) and thalamo-cortical spindle activity (12-15 Hz) during sleep, and their temporal coordination, are considered critical for memory formation. We investigated the potential of slow oscillatory transcranial direct current stimulation (so-tDCS), applied during a daytime nap in a sleep state-dependent manner, to modulate these activity patterns and sleep-related memory consolidation in 16 patients with MCI.

Stimulation significantly increased overall SO and spindle power, amplified spindle power during SO up-phases, and led to stronger synchronization between SO and spindle power fluctuations in electroencephalographic recordings. Moreover, visual declarative memory was improved by so-tDCS compared to sham stimulation, associated with stronger synchronization. These findings indicate a well-tolerated therapeutic approach for disordered sleep physiology and deficits in memory consolidation in MCI patients.
A SUMO-Ubiquitin Relay Recruits Proteasomes to Chromosome Axes to Regulate Meiotic Recombination
Authors: Rao H.B.D. Prasada , Qiao Huanyu , Bhatt Shubhang K. , Bailey Logan R.J. , Tran Hung D. , Bourne Sarah L. , Qiu Wendy , Deshpande Anusha , Sharma Ajay N. , Beebout Connor J. , Pezza Roberto J. , Hunter Neil
Published: December 2016

Meiosis produces haploid gametes through a succession of chromosomal events including pairing, synapsis and recombination. Mechanisms that orchestrate these events remain poorly understood. We found that the SUMO-modification and ubiquitin-proteasomes systems regulate the major events of meiotic prophase in mouse. Interdependent localization of SUMO, ubiquitin and proteasomes along chromosome axes was mediated largely by RNF212 and HEI10, two E3 ligases that are also essential for crossover recombination. RNF212-dependent SUMO conjugation effected a checkpoint-like process that stalls recombination by rendering the turnover of a subset of recombination factors dependent on HEI10-mediated ubiquitylation. We propose that SUMO conjugation establishes a precondition for designating crossover sites via selective protein stabilization. Thus, meiotic chromosome axes are hubs for regulated proteolysis via SUMO-dependent control of the ubiquitin-proteasome system.

One Sentence Summary

Chromosomal events of meiotic prophase in mouse are regulated by proteasome-dependent protein degradation.
Using Single Nucleotide Variations in Single-Cell RNA-Seq to Identify Subpopulations and Genotype-phenotype Linkage
Authors: Poirion Olivier , Zhu Xun , Ching Travers , Garmire Lana X.
Published: December 2016

Despite its popularity, characterization of subpopulations with transcript abundance is subject to a significant amount of noise. We propose to use effective and expressed nucleotide variations (eeSNVs) from scRNA-seq as alternative features for tumor subpopulation identification. We developed a linear modeling framework, SSrGE, to link eeSNVs associated with gene expression. In all the datasets tested, eeSNVs achieve better accuracies than gene expression for identifying subpopulations. Previously validated cancer-relevant genes are also highly ranked, confirming the significance of the method. Moreover, SSrGE is capable of analyzing coupled DNA-seq and RNA-seq data from the same single cells, demonstrating its value in integrating multi-omics single cell techniques. In summary, SNV features from scRNA-seq data have merits for both subpopulation identification and linkage of genotype-phenotype relationship. The method SSrGE is available athttps://github.com/lanagarmire/SSrGE.
Dynamic compensation, parameter identifiability, and equivariances
Authors: Sontag Eduardo
Published: December 2016

A recent paper by Karin, Swisa, Glaser, Dor, and Alon introduced the mathematical notion of dynamical compensation (DC) in biological circuits, arguing that DC helps explain important features of glucose homeostasis as well as other key physiological regulatory mechanisms. The present paper establishes a connection between DC and two well-known notions in systems biology: system equivalence and parameter (un)identifiability. This recasting leads to effective tests for verifying DC in mathematical models.
Bayesian non-central chi regression for neuroimaging
Authors: Wegmann Bertil , Eklund Anders , Villani Mattias
Published: December 2016

We propose a regression model for non-centralχ(NC-χ) distributed functional magnetic resonance imaging (fMRI) and diffusion weighted imaging (DWI) data, with the heteroscedastic Rician regression model as a prominent special case. The model allows both parameters in the NC-χdistribution to be linked to explanatory variables, with the relevant covariates automatically chosen by Bayesian variable selection. A highly efficient Markov chain Monte Carlo (MCMC) algorithm is proposed for simulating from the joint Bayesian posterior distribution of all model parameters and the binary covariate selection indicators. Simulated fMRI data is used to demonstrate that the Rician model is able to localize brain activity much more accurately than the traditionally used Gaussian model at low signal-to-noise ratios. Using a diffusion dataset from the Human Connectome Project, it is also shown that the commonly used approximate Gaussian noise model underestimates the mean diffusivity (MD) and the fractional anisotropy (FA) in the single-diffusion tensor model compared to the theoretically correct Rician model.
Transcriptional study of the ABC transporter-encoding genes in response to fungicide treatment and during plant infection in the phytopathogenic fungusBotrytis cinerea
Authors: Loisel Elise , Goncalves Isabelle R. , Poussereau Nathalie , Grosjean-Cournoyer Marie-Claire , Villalba François , Bruel Christophe
Published: December 2016

The grey mould fungusBotrytis cinereacauses worldwide losses of commercially important fruits, vegetables and ornamentals. Various fungicides, with different modes of action, are effective against this pathogen, but isolates with multiple fungicide-resistance phenotypes (Multi Drug Resistance, MDR) have been observed with increasing frequency. In fungi, ATP binding cassette (ABC) transporters participate in drug efflux and we report here on the parallel transcriptional study of the predicted ABC transporter-encoding genes inB. cinerea.During plant infection, transcription of all of these genes was activated and over-expression was observed for a few of these genes if the plants were treated with a fungicide prior to infection. In the absence of plant, most of the genes were transcriptionally activated in response to two different fungicides. Both common and specific transcriptional signatures were observed.
A Unique Ribosome Signature Reveals Bacterial Translation Initiation Sites
Authors: Giess Adam , Ndah Elvis , Jonckheere Veronique , Van Damme Petra , Valen Eivind
Published: December 2016

While methods for annotation of genes are increasingly reliable the exact identification of the translation initiation site remains a challenging problem. Since the N-termini of proteins often contain regulatory and targeting information developing a robust method for start site identification is crucial. Ribosome profiling reads show distinct patterns of read length distributions around translation initiation sites. These patterns are typically lost in standard ribosome profiling analysis pipelines, when reads from footprints are adjusted to determine the specific codon being translated. Using these unique signatures we build a model capable of predicting translation initiation sites and demonstrate its high accuracy using N-terminal proteomics. Applying this to prokaryotic samples, we re-annotate translation initiation sites and provide evidence of N-terminal truncations and elongations of annotated coding sequences. These re-annotations are supported by the presence of Shine-Dalgarno sequences, structural and sequence based features and N-terminal peptides. Finally, our model identifies 61 novel genes previously undiscovered in the genome.
The Liquid Structure of Elastin
Authors: Rauscher Sarah , Pomès Régis
Published: December 2016

The protein elastin imparts extensibility, elastic recoil, and resilience to tissues including arterial walls, skin, lung alveoli, and the uterus. Elastin and elastin-like peptides are intrinsically disordered hydrophobic proteins that undergo liquid-liquid phase separation upon self-assembly. Despite extensive study for over eighty years, the structure of elastin remains controversial. We use molecular dynamics simulations on a massive scale to elucidate the structural ensemble of aggregated elastin-like peptides. Consistent with the entropic nature of elastic recoil, the aggregated state is stabilized both by the hydrophobic effect and by conformational entropy. The polypeptide backbone forms transient, sparse hydrogen-bonded turns and remains significantly hydrated even as self-assembly triples the extent of nonpolar side-chain contacts. The assembly approaches a maximally-disordered, melt-like state, which may be called the liquid state of proteins. These findings resolve long-standing controversies regarding elastin structure and function and afford insight of broad relevance to the phase separation of disordered proteins.
Behavioural, modeling, and electrophysiological evidence for domain-generality in human metacognition
Authors: Faivre Nathan , Filevich Elisa , Solovey Guillermo , Kühn Simone , Blanke Olaf
Published: December 2016

Metacognition, or the capacity to introspect on one’s own mental states, has been mostly characterized through confidence reports in visual tasks. A pressing question is to what extent the results from visual studies generalize to other domains. Answering this question allows determining whether metacognition operates through shared, domain-general mechanisms, or through idiosyncratic, domain-specific mechanisms. Here, we report three new lines of evidence for decisional and post-decisional mechanisms arguing for the domain-generality of metacognition. First, metacognitive efficiency correlated between auditory, tactile, visual, and audiovisual tasks. Second, confidence in an audiovisual task was best modeled using supramodal formats based on integrated representations of auditory and visual signals. Third, confidence in correct responses involved similar electrophysiological markers for visual and audiovisual tasks that are associated with motor preparation preceding the perceptual judgment. We conclude that the domain-generality of metacognition relies on supramodal confidence estimates and decisional signals that are shared across sensory modalities.
Cellular Orientation Is Guided by Strain Gradients
Authors: Chagnon-Lessard Sophie , Jean-Ruel Hubert , Godin Michel , Pelling Andrew E.
Published: December 2016

The strain-induced reorientation response of cyclically stretched cells has been well characterized in uniform strain fields. In the present study, we comprehensively analyse the behaviour of human fibroblasts subjected to a highly non-uniform strain field within a polymethylsiloxane microdevice. Our results indicate that the strain gradient amplitude and direction regulate cell reorientation through a coordinated gradient avoidance response. We provide critical evidence that strain gradient is a key physical cue that can guide cell organization. Specifically, our work suggests that cells are able to pinpoint the location under the cell of multiple physical cues and integrate this information (strain and strain gradient amplitudes and directions), resulting in a coordinated response. To gain insight into the underlying mechanosensing processes, we studied focal adhesion reorganization and the effect of modulating myosin-II contractility. The extracted focal adhesion orientation distributions are similar to those obtained for the cell bodies, and their density is increased by the presence of stretching forces. Moreover, it was found that the myosin-II activity promoter calyculin-A has little effect on the cellular response, while the inhibitor blebbistatin suppresses cell and focal adhesion alignment and reduces focal adhesion density. These results confirm that similar internal structures involved in sensing and responding to strain direction and amplitude are also key players in strain gradient mechanosensing and avoidance.
Noninvasive Prenatal Screening at Low Fetal Fraction: Comparing Whole-Genome Sequencing and Single-Nucleotide Polymorphism Methods
Authors: Artieri Carlo G. , Haverty Carrie , Evans Eric A. , Goldberg James D. , Haque Imran S. , Yaron Yuval , Muzzey Dale
Published: December 2016

Objective

Performance of noninvasive prenatal screening (NIPS) methodologies when applied to low fetal fraction samples is not well established. The single-nucleotide polymorphism (SNP) method fails samples below a predetermined fetal fraction threshold, whereas some laboratories employing the whole-genome sequencing (WGS) method report aneuploidy calls for all samples. Here, the performance of the two methods was compared to determine which approach actually detects more fetal aneuploidies.

Methods

Computational models were parameterized with up-to-date published data and used to compare the performance of the two methods at calling common fetal trisomies (T21, T18, T13) at low fetal fractions. Furthermore, clinical experience data were reviewed to determine aneuploidy detection rates based on compliance with recent invasive screening recommendations.

Results

The SNP method’s performance is dependent on the origin of the trisomy, and is lowest for the most common trisomies (maternal M1 nondisjunction). Consequently, the SNP method cannot maintain acceptable performance at fetal fractions below ~3%. In contrast, the WGS method maintains high specificity independent of fetal fraction and has >80% sensitivity for trisomies in low fetal fraction samples.

Conclusion

The WGS method will detect more aneuploidies below the fetal fraction threshold at which many labs issue a no-call result, avoiding unnecessary invasive procedures.
Myc/Mycn-mediated glycolysis enhances mouse spermatogonial stem cell self-renewal
Authors: Kanatsu-Shinohara Mito , Tanaka Takashi , Ogonuki Narumi , Ogura Atsuo , Morimoto Hiroko , Cheng Pei Feng , Eisenman Robert N. , Trumpp Andreas , Shinohara Takashi
Published: December 2016

Mycplays critical roles in the self-renewal division of various stem cell types. In spermatogonial stem cells (SSCs),Myccontrols SSC fate decisions becauseMycoverexpression induces enhanced self-renewal division, while depletion ofMax, aMyc-binding partner, leads to meiotic induction. However, the mechanism by whichMycacts on SSC fate is unclear. Here we demonstrate a critical link betweenMyc/Mycngene activity and glycolysis in SSC self-renewal. In SSCs,Myc/Mycnare regulated byFoxo1, whose deficiency impairs SSC self-renewal.Myc/Mycn-deficient SSCs not only undergo limited self-renewal division but also display diminished glycolytic activity. While inhibition of glycolysis decreased SSC activity, chemical stimulation of glycolysis or transfection of activeAkt1orPdpk1(phosphoinositide-dependent protein kinase 1 ) augmented self-renewal division, and long-term SSC cultures were derived from a nonpermissive strain that showed limited self-renewal division. These results suggested thatMyc-mediated glycolysis is an important factor that increases the frequency of SSC self-renewal division.
p38MAPK builds a hyaluronan cancer niche to drive lung tumorigenesis
Authors: Brichkina Anna , Bertero Thomas , Loh Hui Mun , Nguyen Nguyet Thi Minh , Emelyanov Alexander , Rigade Sidwell , Ilie Marius , Hofman Paul , Gaggioli Cedric , Bulavin Dmitry V.
Published: December 2016

Expansion of neoplastic lesions generates the initial signal that instigates the creation of a tumor niche. Nontransformed cell types within the microenvironment continuously coevolve with tumor cells to promote tumorigenesis. Here, we identify p38MAPK as a key component of human lung cancer, and specifically stromal interactomes, which provides an early, protumorigenic signal in the tissue microenvironment. We found that lung cancer growth depends on short-distance cues produced by the cancer niche in a p38-dependent manner. We identified fibroblast-specific hyaluronan synthesis at the center of p38-driven tumorigenesis, which regulates early stromal fibroblast activation, the conversion to carcinoma-associated fibroblasts (CAFs), and cancer cell proliferation. Systemic down-regulation of p38MAPK signaling in a knock-in model with substitution of activating Tyr182 to phenylalanine or conditional ablation of p38 in fibroblasts has a significant tumor-suppressive effect on K-ras lung tumorigenesis. Furthermore, both Kras-driven mouse lung tumors and orthotopically grown primary human lung cancers show a significant sensitivity to both a chemical p38 inhibitor and an over-the-counter inhibitor of hyaluronan synthesis. We propose that p38MAPK–hyaluronan-dependent reprogramming of the tumor microenvironment plays a critical role in driving lung tumorigenesis, while blocking this process could have far-reaching therapeutic implications.
An ensemble of regulatory elements controls Runx3 spatiotemporal expression in subsets of dorsal root ganglia proprioceptive neurons
Authors: Appel Elena , Weissmann Sarit , Salzberg Yehuda , Orlovsky Kira , Negreanu Varda , Tsoory Michael , Raanan Calanit , Feldmesser Ester , Bernstein Yael , Wolstein Orit , Levanon Ditsa , Groner Yoram
Published: December 2016

The Runx3 transcription factor is essential for development and diversification of the dorsal root ganglia (DRGs) TrkC sensory neurons. In Runx3-deficient mice, developing TrkC neurons fail to extend central and peripheral afferents, leading to cell death and disruption of the stretch reflex circuit, resulting in severe limb ataxia. Despite its central role, the mechanisms underlying the spatiotemporal expression specificities of Runx3 in TrkC neurons were largely unknown. Here we first defined the genomic transcription unit encompassing regulatory elements (REs) that mediate the tissue-specific expression of Runx3. Using transgenic mice expressing BAC reporters spanning the Runx3 locus, we discovered three REs—dubbed R1, R2, and R3—that cross-talk with promoter-2 (P2) to drive TrkC neuron-specific Runx3 transcription. Deletion of single or multiple elements either in the BAC transgenics or by CRISPR/Cas9-mediated endogenous ablation established the REs’ ability to promote and/or repress Runx3 expression in developing sensory neurons. Our analysis reveals that an intricate combinatorial interplay among the three REs governs Runx3 expression in distinct subtypes of TrkC neurons while concomitantly extinguishing its expression in non-TrkC neurons. These findings provide insights into the mechanism regulating cell type-specific expression and subtype diversification of TrkC neurons in developing DRGs.
Genetic compendium of 1511 human brains available through the UK Medical Research Council Brain Banks Network Resource
Authors: Keogh Michael J. , Wei Wei , Wilson Ian , Coxhead Jon , Ryan Sarah , Rollinson Sara , Griffin Helen , Kurzawa-Akanbi Marzena , Santibanez-Koref Mauro , Talbot Kevin , Turner Martin R. , McKenzie Chris-Anne , Troakes Claire , Attems Johannes , Smith Colin , Al Sarraj Safa , Morris Chris M. , Ansorge Olaf , Pickering-Brown Stuart , Ironside James W. , Chinnery Patrick F.
Published: December 2016

Given the central role of genetic factors in the pathogenesis of common neurodegenerative disorders, it is critical that mechanistic studies in human tissue are interpreted in a genetically enlightened context. To address this, we performed exome sequencing and copy number variant analysis on 1511 frozen human brains with a diagnosis of Alzheimer's disease (AD, n = 289), frontotemporal dementia/amyotrophic lateral sclerosis (FTD/ALS, n = 252), Creutzfeldt-Jakob disease (CJD, n = 239), Parkinson's disease (PD, n = 39), dementia with Lewy bodies (DLB, n = 58), other neurodegenerative, vascular, or neurogenetic disorders (n = 266), and controls with no significant neuropathology (n = 368). Genomic DNA was extracted from brain tissue in all cases before exome sequencing (Illumina Nextera 62 Mb capture) with variants called by FreeBayes; copy number variant (CNV) analysis (Illumina HumanOmniExpress-12 BeadChip); C9orf72 repeat expansion detection; and APOE genotyping. Established or likely pathogenic heterozygous, compound heterozygous, or homozygous variants, together with the C9orf72 hexanucleotide repeat expansions and a copy number gain of APP, were found in 61 brains. In addition to known risk alleles in 349 brains (23.9% of 1461 undergoing exome sequencing), we saw an association between rare variants in GRN and DLB. Rare CNVs were found in <1.5% of brains, including copy number gains of PRPH that were overrepresented in AD. Clinical, pathological, and genetic data are available, enabling the retrieval of specific frozen brains through the UK Medical Research Council Brain Banks Network. This allows direct access to pathological and control human brain tissue based on an individual's genetic architecture, thus enabling the functional validation of known genetic risk factors and potentially pathogenic alleles identified in future studies.
Neutron total scattering of crystalline materials in the gigapascal regime
Authors: Playford Helen Y. , Tucker Matthew G. , Bull Craig L.
Published: December 2016

Neutron total scattering of disordered crystalline materials provides direct experimental access to the local (short-range) structure. The ways in which this local structure agrees (or disagrees) with the long-range crystal structure can provide important insight into structure–property relationships. High-pressure neutron diffraction using a Paris–Edinburgh (P–E) pressure cell allows experimenters to explore the ways in which materials are affected by pressure, can reveal new synthetic routes to novel functional materials and has important applications in many areas, including geology, engineering and planetary science. However, the combination of these two experimental techniques poses unique challenges for both data collection and analysis. In this paper it is shown that, with only minor modifications to the standard P–E press setup, high-quality total scattering data can be obtained from crystalline materials in the gigapascal pressure regime on the PEARL diffractometer at ISIS. The quality of the data is assessed through the calculation of coordination numbers and the use of reverse Monte Carlo refinements. The time required to collect data of sufficient quality for detailed analysis is assessed and is found to be of the order of 8 h for a quartz sample. Finally, data from the perovskite LaCo0.35Mn0.65O3 are presented and reveal that PEARL total scattering data offer the potential of extracting local structural information from complex materials at high pressure.
Evolution of the pore structure during the early stages of the alkali-activation reaction: anin situsmall-angle neutron scattering investigation
Authors: White Claire E. , Olds Daniel P. , Hartl Monika , Hjelm Rex P. , Page Katharine
Published: December 2016

The long-term durability of cement-based materials is influenced by the pore structure and associated permeability at the sub-micrometre length scale. With the emergence of new types of sustainable cements in recent decades, there is a pressing need to be able to predict the durability of these new materials, and therefore nondestructive experimental techniques capable of characterizing the evolution of the pore structure are increasingly crucial for investigating cement durability. Here, small-angle neutron scattering is used to analyze the evolution of the pore structure in alkali-activated materials over the initial 24 h of reaction in order to assess the characteristic pore sizes that emerge during these short time scales. By using a unified fitting approach for data modeling, information on the pore size and surface roughness is obtained for a variety of precursor chemistries and morphologies (metakaolin- and slag-based pastes). Furthermore, the impact of activator chemistry is elucidatedviathe analysis of pastes synthesized using hydroxide- and silicate-based activators. It is found that the main aspect influencing the size of pores that are accessible using small-angle neutron scattering analysis (approximately 10–500 Å in diameter) is the availability of free silica in the activating solution, which leads to a more refined pore structure with smaller average pore size. Moreover, as the reaction progresses the gel pores visible using this scattering technique are seen to increase in size.
Hydrogen bonds and van der Waals forces as tools for the construction of a herringbone pattern in the crystal structure of hexane-1,6-diaminium hexane-1,6-diyl bis(hydrogen phosphonate)
Authors: Reiss Guido J. , Megen Martin van , Frank Walter
Published: December 2016

The asymmetric unit of the title salt, [H3N(CH2)6NH3][(HO)O2P(CH2)6PO2(OH)], consists of one half of a hexane-1,6-diaminium dication and one half of a hexane-1,6-diyl bis(hydrogen phosphonate) dianion. Both are located around different centres of inversion (Wyckoff sites: 2aand 2d) of the space groupP21/c. The shape of the hexane-1,6-diaminium cation is best described as a double hook. Both aminium groups as well as the two attached CH2groups are turned out from the plane of the central four C atoms. In contrast, all six C atoms of the dianion are almost in a plane. The hydrogen phosphonate (–PO3H) groups of the anions and the aminium groups of the cations form two-dimensional O—H... and O—H...N hydrogen-bonded networks parallel to theacplane, built up from ten-membered and twelve-membered ring motifs with graph-set descriptorsR33(10) andR54(12), respectively. These networks are linked by the alkylene chains of the anions and cations. The resulting three-dimensional network shows a herringbone pattern, which resembles the parent structures 1,6-diaminohexane and hexane-1,6-diphosphonic acid.
Crystal structure of μ-carbonyl-1:2κ2C:C-carbonyl-1κC-(1η5-cyclopentadienyl)iodido-2κI-[μ-2-(pyridin-2-yl)ethene-1,1-diyl-1κC1:2κ2N,C1]ironpalladium(Fe—Pd) benzene monosolvate
Authors: Verpekin Victor V. , Kreindlin Arkadii Z. , Semeikin Oleg V. , Smol'yakov Alexander F. , Dolgushin Fedor M. , Chudin Oleg S. , Ustynyuk Nikolai A.
Published: December 2016

The reaction of Cp(CO)2FeI with 2-ethynylpyridine under Sonogashira conditions [5% PdCl2(PPh3)2, 10% CuI, THF–NEt3(2:1)] afforded the title binuclear μ-pyridylvinylidene FePd complex (FePd1) as a benzene solvate, [FePd(C5H5)(C7H5N)I(CO)2]·C6H6, in a very low yield rather than the expected irono-pyridylethynyl complex Cp(CO)2Fe—C[triple-bond]C-(2-C5H4N). The Fe and Pd atoms inFePd1are bridged by carbonyl and pyridylvinylidene ligands, the pyridyl N atom being bonded to the palladium atom. The use of equimolar amounts of PdCl2increases the yield ofFePd1to 12%. The reaction pathway leading toFePd1is proposed.
Crystal structure and absolute configuration of (3aR,3′aR,7aS,7′aS)-2,2,2′,2′-tetramethyl-3a,6,7,7a,3′a,6′,7′,7′a-octahydro-4,4′-bi[1,3-benzodioxolyl], obtained from a Pd-catalyzed homocoupling reaction
Authors: Macías Mario A. , Pandolfi Enrique , Schapiro Valeria , Silveira Gustavo P. , Vilela Guilherme D. , Suescun Leopoldo
Published: December 2016

The absolute configuration,i.e.(3aR,3′aR,7aS,7′aS), of the title compound, C18H26O4, synthesizedviaa palladium-catalyzed homocoupling reaction, was determined on the basis of the synthetic pathway and was confirmed by X-ray diffraction. The homocoupled molecule is formed by two chemically identical moieties built up from two five- and six-membered fused rings. The supramolecular assembly is controlled mainly by C—H...O interactions that lead to the formation of hydrogen-bonded chains of molecules along the [001] direction, while weak dipolar interactions and van der Waals forces hold the chains together in the crystal structure.
Crystal structure of (2R*,3aR*)-2-phenylsulfonyl-2,3,3a,4,5,6-hexahydropyrrolo[1,2-b]isoxazole
Authors: Hernández Yaiza , Marcos Isidro , Garrido Narciso M. , Sanz Francisca , Diez David
Published: December 2016

The title compound, C12H15NO3S, was prepared by 1,3-dipolar cycloaddition of 3,4-dihydro-2H-pyrrole 1-oxide and phenyl vinyl sulfone. In the molecule, both fused five-membered rings display a twisted conformation. In the crystal, C—H...O hydrogen bonds link neighbouring molecules, forming chains running parallel to thebaxis.
Crystal structure of a rare trigonal bipyramidal titanium(IV) coordination complex: trichlorido(3,3′-di-tert-butyl-2′-hydroxy-5,5′,6,6′-tetramethyl-1,1′-biphenyl-2-olato-κO2)(tetrahydrofuran-κO)titanium(IV)
Authors: Kim Yun Young , Tanski Joseph M.
Published: December 2016

The title compound, [Ti(C24H33O2)Cl3(C4H8O)], is a rare example of a trigonal–bipyramidal titanium coordination complex with three chloride and two oxygen donor ligands. The asymmetric unit contains two independent molecules having essentially the same conformation. The molecules feature the titanium(IV) metal cation complexed with three chloride ligands, a tetrahydrofuran molecule, and one oxygen atom from the resolved ligand precursor (R)-(+)-5,5′,6,6′-tetramethyl-3,3′-di-t-butyl-1,1′-biphenyl-2,2′-diol, where the remaining phenolic hydrogen atom engages in intermolecular O—H...Cl hydrogen bonding. In one molecule, the THF ligand is disordered over two orientations with refined site occupancies of 0.50 (3).
Crystal structure of dirubidium hydrogen citrate from laboratory X-ray powder diffraction data and DFT comparison
Authors: Rammohan Alagappa , Kaduk James A.
Published: December 2016

The crystal structure of dirubidium hydrogen citrate, 2Rb+·HC6H5O72−, has been solved and refined using laboratory X-ray powder diffraction data, and optimized using density functional techniques. The un-ionized carboxylic acid group forms helical chains of very strong hydrogen bonds (O...O ∼ 2.42 Å) along thebaxis. The hydroxy group participates in a chain of intra- and intermolecular hydrogen bonds along thecaxis. These hydrogen bonds result in corrugated hydrogen-bonded layers in thebcplane. The Rb+cations are six-coordinate, and share edges and corners to form layers in theabplane. The interlayer contacts are composed of the hydrophobic methylene groups.