bluuebunny/crossref_metadata_2025 huggingface dataset:
Six percent loss of genetic variation in wild populations since the industrial revolution
Authors: Leigh D.M. , Hendry A.P. , Vázquez-Domínguez E. , Friesen V. L.
Published: December 2018

Genetic variation underpins population fitness and adaptive potential1,2. Thus it plays a key role in any species’ probability of long-term persistence, particularly under global climate change. Genetic variation can be lost in a single generation but its replenishment may take hundreds of generations3. For that reason safeguarding genetic variation is considered fundamental to maintaining biodiversity, and is an Aichi Target for 20204. As human activities are driving declines in many wild populations5, genetic variation is also likely declining. However the magnitude of ongoing genetic variation loss has not been assessed, despite its importance. Here we show a 6% decline in within-population genetic variation of wild organisms since the industrial revolution. The erosion of genetic variation has been most severe for island species, with an 18% average decline. We also identified several key taxonomic and geographic information gaps that must be urgently addressed. Our results are consistent with single time-point meta-analyses that indicated genetic variation is likely declining6,7. However, our results represent the first confirmation of a global decline, and estimate of the magnitude of the genetic variation lost from wild populations.
Microstructural and Functional Gradients are Increasingly Dissociated in Transmodal Cortices
Authors: Paquola Casey , Vos De Wael Reinder , Wagstyl Konrad , Bethlehem Richard A.I. , Hong Seok-Jun , Seidlitz Jakob , Bullmore Edward T. , Evans Alan C. , Misic Bratislav , Margulies Daniel S. , Smallwood Jonathan , Bernhardt Boris C.
Published: December 2018

While the role of cortical microstructure in organising neural function is well established, it remains unclear how structural constraints can give rise to more flexible elements of cognition. While non-human primate research has demonstrated a close structure-function correspondence, the relationship between microstructure and function remains poorly understood in humans, in part because of the reliance onpost mortemanalyses which cannot be directly related to functional data. To overcome this barrier, we developed a novel approach to model the similarity of microstructural profiles sampled in the direction of cortical columns. Our approach was initially formulated based on an ultra-high-resolution 3D histological reconstruction of an entire human brain and then translated to myelin-sensitive MRI data in a large cohort of healthy adults. This novel method identified a system-level gradient of microstructural differentiation traversing from primary sensory to limbic regions that followed shifts in laminar differentiation and cytoarchitectural complexity. Importantly, while microstructural and functional gradients described a similar hierarchy, they became increasingly dissociated in transmodal default mode and fronto-parietal networks. Meta analytic decoding of these topographic dissociations highlighted involvement in higher-level aspects of cognition such as cognitive control and social cognition. Our findings demonstrate a relative decoupling of macroscale functional from microstructural gradients in transmodal regions, which likely contributes to the flexible role these regions play in human cognition.
Lineage EM Algorithm for Inferring Latent States from Cellular Lineage Trees
Authors: Nakashima So , Sughiyama Yuki , Kobayashi Tetsuya J.
Published: December 2018

Phenotypic variability in a population of cells can work as the bet-hedging of the cells under an unpredictably changing environment, the typical example of which is the bacterial persistence. To understand the strategy to control such phenomena, it is indispensable to identify the phenotype of each cell and its inheritance. Although recent advancements in microfluidic technology offer us useful lineage data, they are insufficient to directly identify the phenotypes of the cells. An alternative approach is to infer the phenotype from the lineage data by latent-variable estimation. To this end, however, we must resolve the bias problem in the inference from lineage called survivorship bias. In this work, we clarify how the survivor bias distorts statistical estimations. We then propose a latent-variable estimation algorithm without the survivorship bias from lineage trees based on an expectation-maximization (EM) algorithm, which we call Lineage EM algorithm (LEM). LEM provides a statistical method to identify the traits of the cells applicable to various kinds of lineage data.
Asynchronous non-invasive high-speed BCI speller with robust non-control state detection
Authors: Nagel Sebastian , Spüler Martin
Published: December 2018

Brain-Computer Interfaces (BCIs) enable users to control a computer by using pure brain activity. Recent BCIs based on visual evoked potentials (VEPs) have shown to be suitable for high-speed communication. However, all recent high-speed BCIs are synchronous, which means that the system works with fixed time slots so that the user is not able to select a command at his own convenience, which poses a problem in real-world applications. In this paper, we present the first asynchronous high-speed BCI with robust distinction between intentional control (IC) and non-control (NC), with a nearly perfect NC state detection of only 0.075 erroneous classifications per minute. The resulting asynchronous speller achieved an average information transfer rate (ITR) of 122.7 bit/min using a 32 target matrix-keyboard. Since the method is based on random stimulation patterns it allows to use an arbitrary number of targets for any application purpose, which was shown by using an 55 target German QWERTZ-keyboard layout which allowed the participants to write an average of 16.1 (up to 30.7) correct case-sensitive letters per minute. As the presented system is the first asynchronous high-speed BCI speller with a robust non-control state detection, it is an important step for moving BCI applications out of the lab and into real-life.
Functional analyses of the horizontally acquired Phytophaga glycoside hydrolase family 45 (GH45) proteins reveal distinct functional characteristics
Authors: Busch André , Danchin Etienne G.J. , Pauchet Yannick
Published: December 2018

Cellulose, a major polysaccharide of the plant cell wall, consists of β-1,4-linked glucose moieties forming a molecular network recalcitrant to enzymatic breakdown. Although cellulose is potentially a rich source of energy, the ability to degrade it is rare in animals and was believed to be present only in cellulolytic microbes. Recently, it has become clear that some animals encode endogenous cellulases belonging to several glycoside hydrolase families (GHs), including GH45. GH45s are distributed patchily among the Metazoa and, in insects, are encoded only by the genomes of Phytophaga beetles. This study aims to understand both the enzymatic properties and the evolutionary history of GH45s in these beetles. To this end, we tested the enzymatic abilities of 37 GH45s derived from five species of Phytophaga beetles and learned that beetle-derived GH45s degrade three different substrates: amorphous cellulose, xyloglucan and glucomannan. Our phylogenetic and gene structure analyses indicate that at least one gene encoding a putative cellulolytic GH45 was present in the last common ancestor of the Phytophaga, and that GH45 xyloglucanases evolved several times independently in these beetles. The most closely related clade to Phytophaga GH45s contained fungal sequences, suggesting this GH family was acquired by horizontal gene transfer from fungi. Other than in insects, arthropod GH45s do not share a common origin and appear to have emerged at least three times independently.
Global increase in circRNA levels in myotonic dystrophy
Authors: Czubak Karol , Taylor Katarzyna , Piasecka Agnieszka , Sobczak Krzysztof , Kozlowska Katarzyna , Philips Anna , Sedehizadeh Saam , Brook J. David , Wojciechowska Marzena , Kozlowski Piotr
Published: December 2018

Splicing aberrations induced as a consequence of the sequestration of MBNL splicing factors on the DMPK transcript, which contains expanded CUG repeats, present a major pathomechanism of myotonic dystrophy type 1 (DM1). As MBNLs may also be important factors involved in the biogenesis of circular RNAs (circRNAs), we hypothesized that the level of circRNAs would be decreased in DM1. To test this hypothesis, we selected twenty well-validated circRNAs and analyzed their levels in several experimental systems (e.g., cell lines, DM muscle tissues, and a mouse model of DM1) using droplet digital PCR assays. We also explored the global level of circRNAs using two RNA-Seq datasets of DM1 muscle samples. Contrary to our original hypothesis, our results consistently showed a global increase in circRNA levels in DM1 and we identified numerous circRNAs that were increased in DM1. We also identified many genes (including muscle-specific genes) giving rise to numerous (>10) circRNAs. Thus, this study is the first to show an increase in global circRNA levels in DM1. We also provided preliminary results showing the association of circRNA level with muscle weakness and alternative splicing changes that are biomarkers of DM1 severity.

Author Summary

Recently, a great deal of interest has been focused on a new class of RNA molecules called circular RNAs (circRNAs). To date, thousands of circRNAs have been found in different human cells/tissues. Although the function of circRNAs remains mostly unknown, circRNAs have emerged as an important component of the RNA-RNA and RNA-protein interactome. Thus, intensive efforts are being made to fully understand the biology and function of circRNAs, especially their role in human diseases. As an important role in the biogenesis of circRNA may be played by MBNL splicing factors, in this study we used DM1 (to a lesser extent, DM2) as a natural model in which the level of MBNLs is decreased. In contrast to the expected effect, our results consistently showed a global increase in circRNA levels in DM1. As a consequence, whole genome transcriptome analysis revealed dozens of circRNAs with significantly altered (mostly increased) levels in DM1. Furthermore, we observed that the circRNA levels were in many cases strongly associated with DM1 severity.
Extensive genetic differentiation between recently evolved sympatric Arctic charr morphs
Authors: Guðbrandsson Jóhannes , Kapralova Kalina H. , Franzdóttir Sigríður R. , Bergsveinsdóttir Þóra Margrét , Hafstað Völundur , Jónsson Zophonías O. , Snorrason Sigurður S. , Pálsson Arnar
Published: December 2018

The availability of diverse ecological niches can promote adaptation of trophic specializations and related traits, as has been repeatedly observed in evolutionary radiations of freshwater fish. The role of genetics, environment and history in ecologically driven divergence and adaptation, can be studied on adaptive radiations or populations showing ecological polymorphism. Salmonids, especially theSalvelinusgenus, are renowned for both phenotypic diversity and polymorphism. Arctic charr (Salvelinus alpinus) invaded Icelandic streams during the glacial retreat (about 10,000 years ago) and exhibits many instances of sympatric polymorphism. Particularly well studied are the four morphs in Lake Þingvallavatn in Iceland. The small benthic (SB), large benthic (LB), planktivorous (PL) and piscivorous (PI) charr differ in many regards, including size, form and life history traits. To investigate relatedness and genomic differentiation between morphs we identified variable sites from RNA-sequencing data from three of those morphs, and verified 22 variants in population samples. The data reveal genetic differences between the morphs, with the two benthic morphs being more similar and the PL-charr more genetically different. The markers with high differentiation map to all linkage groups, suggesting ancient and pervasive genetic separation of these three morphs. Furthermore, GO analyses suggest differences in collagen metabolism, odontogenesis and sensory systems between PL-charr and the benthic morphs. Genotyping in population samples from all four morphs confirms the genetic separation and indicates that the PI-charr are less genetically distinct than the other three morphs. The genetic separation of the other three morphs indicates certain degree of reproductive isolation. The extent of gene flow between the morphs and the nature of reproductive barriers between them remain to be elucidated.
Reduced Resting-State Connectivity in the Precuneus is correlated with Apathy in Patients with Schizophrenia
Authors: Forlim Caroline Garcia , Klock Leonie , Bächle Johanna , Stoll Laura , Giemsa Patrick , Fuchs Marie , Schoofs Nikola , Montag Christiane , Gallinat Jürgen , Kühn Simone
Published: December 2018

A diagnosis of schizophrenia is associated with a heterogeneous psychopathology including positive and negative symptoms. The disconnection hypothesis, an early pathophysiological framework conceptualizes the diversity of symptoms as a result from disconnections in neural networks. In line with this hypothesis, previous neuroimaging studies of patients with schizophrenia reported alterations within the default mode network (DMN), the most prominent network at rest.

Aim of the present study was to investigate the functional connectivity during rest in patients with schizophrenia and healthy individuals and explore whether observed functional alterations are related to the psychopathology of patients. Therefore, functional magnetic resonance images at rest were recorded of 35 patients with schizophrenia and 41 healthy individuals. Independent component analysis (ICA) was used to extract resting state networks.

Comparing ICA results between groups indicated alterations only within the network of the DMN. More explicitly, reduced connectivity in the precuneus was observed in patients with schizophrenia compared to healthy controls. Connectivity in this area was negatively correlated with the severity of negative symptoms, more specifically with the domain of apathy.

Taken together, the current results provide further evidence for a role DMN alterations might play in schizophrenia and especially in negative symptom such as apathy.
Metacommunity-scale biodiversity regulation and the self-organized emergence of macroecological patterns
Authors: O’Sullivan Jacob D. , Knell Robert J. , Rossberg Axel G.
Published: December 2018

There exist a number of key macroecological patterns whose ubiquity suggests the spatio-temporal structure of ecological communities is governed by some universal mechanisms. The nature of these mechanisms, however, remains poorly understood. Here we probe spatio-temporal patterns in species richness and community composition using a simple metacommunity assembly model. Despite making noa prioriassumptions regarding biotic spatial structure or the distribution of biomass across species, model metacommunities self-organize to reproduce well documented patterns including characteristic species abundance distributions, range size distributions and species area relations. Also in agreement with observations, species richness in our model attains an equilibrium despite continuous species turnover. Crucially, it is in the neighbourhood of the equilibrium that we observe the emergence of these key macroecological patterns. Biodiversity equilibria in models occur due to the onset of ecological structural instability, a population-dynamical mechanism. This strongly suggests a causal link between local community processes and macroecological phenomena.

Should this manuscript be accepted all simulation data supporting the results will be archived in a public repository and the data DOI will be included at the end of the article
Sound source localization with varying amount of visual information in virtual reality
Authors: Ahrens Axel , Lund Kasper Duemose , Marschall Marton , Dau Torsten
Published: December 2018

To achieve accurate spatial auditory perception, subjects typically require personal head-related transfer functions (HRTFs) and the freedom for head movements. Loudspeaker-based virtual sound environments allow for realism without individualized measurements. To study audio-visual perception in realistic environments, the combination of spatially tracked head mounted displays (HMDs), also known as virtual reality glasses, and virtual sound environments may be valuable. However, HMDs were recently shown to affect the subjects’ HRTFs and thus might influence sound localization performance. Furthermore, due to limitations of the reproduction of visual information on the HMD, audio-visual perception might be influenced. Here, a sound localization experiment was conducted both with and without an HMD and with a varying amount of visual information provided to the subjects. Furthermore, interaural time and level difference errors (ITDs and ILDs) as well as spectral perturbations induced by the HMD were analyzed and compared to the perceptual localization data. The results showed a reduction of the localization accuracy when the subjects were wearing an HMD and when they were blindfolded. The HMD-induced error in azimuth localization was found to be larger in the left than in the right hemisphere. Thus, the errors in ITD and ILD can only partly account for the perceptual differences. When visual information of the limited set of source locations was provided, the localization error induced by the HMD was found to be negligible. Presenting visual information of hand-location, room dimensions, source locations and pointing feedback on the HMD revealed similar effects as previously shown in real environments.
Nanopore sequencing significantly improves genome assembly of the eukaryotic protozoan parasite Trypanosoma cruzi
Authors: Diaz-Viraque Florencia , Pita Sebastian , Greif Gonzalo , Moreira de Souza Rita de Cassia , Iraola Gregorio , Robello Carlos
Published: December 2018

Chagas disease was described by Carlos Chagas, who first identified the parasite Trypanosoma cruzi from a two-year-old girl called Berenice. Many T. cruzi sequencing projects based on short reads have demonstrated that genome assembly and downstream comparative analyses are extremely challenging in this species, given that half of its genome is composed of repetitive sequences. Here, we report de novo assemblies, annotation and comparative analyses of the Berenice strain using a combination of Illumina short reads and MinION long reads. Our work demonstrates that Nanopore sequencing improves T. cruzi assembly contiguity and increases the assembly size in ~16 Mb. Specifically, we found that assembly improvement also refines the completeness of coding regions for both single copy genes and repetitive transposable elements. Beyond its historical and epidemiological importance, Berenice constitutes a fundamental resource since it now represents the best-quality assembly available for TcII, a highly prevalent lineage causing human infections in South America. The availability of Berenice genome expands the known genetic diversity of T. cruzi and facilitates more comprehensive evolutionary inferences. Our work represents the first report of Nanopore technology used to resolve complex protozoan genomes, supporting its subsequent application for improving trypanosomatid and other highly repetitive genomes.
A quantitative inventory of yeast P body proteins reveals principles of composition and specificity
Authors: Xing Wenmin , Muhlrad Denise , Parker Roy , Rosen Michael K.
Published: December 2018

P bodies are archetypal biomolecular condensates that concentrate proteins and RNA without a surrounding membrane. While dozens of P body proteins are known, the concentrations of components in the compartment have not been measured. We used live cell imaging to generate a quantitative inventory of the major proteins in yeast P bodies. Only 7 proteins are highly concentrated in P bodies (5.1-15 uM); the 24 others examined are appreciably lower (most ≤ 2.6 uM). P body concentration correlates inversely with cytoplasmic exchange rate. Sequence elements driving Dcp2 concentration into P bodies are distributed across the protein and act cooperatively. Our data indicate that P bodies, and probably other condensates, are biochemically simpler than suggested by proteomic analyses, with implications for specificity, reconstitution and evolution.
Bayesian decision theoretic design of two-founder experimental crosses given diallel data
Authors: Keele Gregory R. , Maurizio Paul L. , Oreper Daniel , Valdar William
Published: December 2018

In designing experimental crosses of inbred strains of model organisms, researchers must make a number of decisions. These include the selection of the appropriate strains, the cross design (eg. F2 intercross), and the number of progeny to collect (sample size). These decisions strongly influence the potential for a successful quantitative trait locus (QTL) mapping experiment; good design decisions will lead to efficient and effective science. Thus experimental design deserves careful consideration and planning. Experimental outcomes can be quantified through utility functions using a Bayesian decision theoretic approaches. For QTL mapping experiments, the power to map a QTL is an appealing utility function to maximize. Using any utility function to aid in experimental design will be dependent on assumptions, such as the QTL effect size in the case of power. Rather than arbitrarily selecting QTL effect size values, they can be estimated from pilot data using a Bayesian hierarchical model. The information in the pilot data can be propagated to the utility function, using Markov Chain Monte Carlo (MCMC) to sample from the posterior distribution. Key features of this approach include: 1) distributional summaries of utility, which are preferable to point estimates, and 2) a comprehensive search of the experimental space of crosses of inbred lines for well-designed experiments. We evaluate this Bayesian theoretic approach using diallel crosses as the pilot data. We present results from simulations as well as present examples from both Mendelian and complex traits in the founder strains of the mouse Collaborative Cross. All analyses were performed using our R package, DIDACT (Diallel-Informed Decision theoretic Approach for Crosses Tool), developed to perform Bayesian cross selection based on diallel pilot data.
MitoZ: A toolkit for mitochondrial genome assembly, annotation and visualization
Authors: Meng Guanliang , Li Yiyuan , Yang Chentao , Liu Shanlin
Published: December 2018

Mitochondrial genome (mitogenome) plays important roles in evolutionary and ecological studies. It becomes routine to utilize multiple genes on mitogenome or the entire mitogenomes to investigate phylogeny and biodiversity of focal groups with the onset of High Throughput Sequencing technologies. We developed a mitogenome toolkit MitoZ, consisting of independent modules ofde novoassembly, findMitoScaf, annotation and visualization, that can generate mitogenome assembly together with annotation and visualization results from HTS raw reads. We evaluated its performance using a total of 50 samples of which mitogenomes are publicly available. The results showed that MitoZ can recover more full-length mitogenomes with higher accuracy compared to the other available mitogenome assemblers. Overall, MitoZ provides a one-click solution to construct the annotated mitogenome from HTS raw data and will facilitate large scale ecological and evolutionary studies. MitoZ is free open source software distributed under GPLv3 license and available athttps://github.com/linzhi2013/MitoZ.
Clustering based approach for population level identification of condition-associated T-cell receptor β-chain CDR3 sequences
Authors: Yohannes Dawit A. , Kaukinen Katri , Kurppa Kalle , Saavalainen Päivi , Greco Dario
Published: December 2018

Motivation

Deep immune receptor sequencing, Repseq, provides unprecedented opportunities to identify condition-associated T-cell clones, represented by T-cell receptor (TCR) CDR3 sequences. TCR profiling has potential value for increasing immunopathological understanding of various diseases, and holds considerable clinical relevance. However, due to the immense diversity of the immune repertoire, identification of condition relevant TCR CDR3s from total repertoires has so far been limited either to mostly “public” CDR3 sequences, which are shared across unrelated individuals, or to comparisons of CDR3 frequencies from multiple samples from the same individual. A methodology for the identification of condition-associated TCR CDR3s by population level comparison of groups of Repseq samples is currently lacking.

Results

We implemented a computational pipeline that allows population level comparison of Repseq sample groups at the level of the immune repertoire sub-units that are shared across individuals. These sub-units (or sub-repertoires) represent shared immuno-genomic features across individuals that potentially encode common signatures in the immune response to antigens. The method first performs unsupervised clustering of CDR3 sequences within each sample based on their similarity in nucleotide or amino acid subsequence frequency. Next, it finds matching clusters across samples, the immune sub-repertoires, and performs statistical differential abundance testing at the level of the identified sub-repertoires. We applied the method on total TCR CDR3β Repseq datasets of celiac disease patients in gluten exposed and unexposed conditions, as well as on public dataset of yellow fever vaccination volunteers before and after immunization. The method successfully identified condition-associated CDR3β sequences, as evidenced by considerable agreement of TRBV-gene and positional amino acid usage patterns in the detected CDR3β sequences with previously known CDR3β species relevant to celiac disease. The method also recovered significantly high numbers of previously known CDR3β sequences, relevant to each condition than would be expected by chance. We conclude that immune sub-repertoires of similar immuno-genomic features, shared across unrelated individuals, encode common immunological information. Moreover, they can serve as viable units of population level immune repertoire comparison, serving as proxy for identification of condition-associated CDR3 sequences.
How long do Red Queen dynamics survive under genetic drift? A comparative analysis of evolutionary and eco-evolutionary models
Authors: Schenk Hanna , Schulenburg Hinrich , Traulsen Arne
Published: December 2018

Background

Red Queen dynamics are defined as long term co-evolutionary dynamics, often with oscillations of genotype abundances driven by fluctuating selection in host-parasite systems. Much of our current understanding of these dynamics is based on theoretical concepts explored in mathematical models that are mostly (i) deterministic, inferring an infinite population size and (ii) evolutionary, thus ecological interactions that change population sizes are excluded. Here, we recall the different mathematical approaches used in the current literature on Red Queen dynamics. We then compare models from game theory (evo) and classical theoretical ecology models (eco-evo), that are all derived from individual interactions and are thus intrinsically stochastic. We assess the influence of this stochasticity through the time to the first loss of a genotype within a host or parasite population.

Results

The time until the first genotype is lost (“extinction time”), is shorter when ecological dynamics, in the form of a changing population size, is considered. Furthermore, when individuals compete only locally with other individuals extinction is even faster. On the other hand, evolutionary models with a fixed population size and competition on the scale of the whole population prolong extinction and therefore stabilise the oscillations. The stabilising properties of intraspecific competitions become stronger when population size is increased and the deterministic part of the dynamics gain influence. In general, the loss of genotype diversity can be counteracted with mutations (or recombination), which then allow the populations to recurrently undergo negative frequency-dependent selection dynamics and selective sweeps.

Conclusion

Although the models we investigated are equal in their biological motivation and interpretation, they have diverging mathematical properties both in the derived deterministic dynamics and the derived stochastic dynamics. We find that models that do not consider intraspecific competition and that include ecological dynamics by letting the population size vary, lose genotypes – and thus Red Queen oscillations – faster than models with competition and a fixed population size.
Integrated use of LC/MS/MS and LC/Q-TOF/MS targeted metabolomics with automated label-free microscopy for quantification of purine metabolites in cultured mammalian cells
Authors: Eric Nybo S. , Lamberts Jennifer T.
Published: December 2018

Purine metabolites have been implicated as clinically relevant biomarkers of worsening or improving Parkinson’s disease (PD) progression. However, the identification of purine molecules as biomarkers in PD has largely been determined using non-targeted metabolomics analysis. The primary goal of this study was to develop an economical targeted metabolomics approach for the routine detection of purine molecules in biological samples. Specifically, this project utilized LC/MS/MS and LC/QTOF/MS to accurately quantify levels of six purine molecules in samples from cultured N2a murine neuroblastoma cells. The targeted metabolomics workflow was integrated with automated label-free digital microscopy, which enabled normalization of purine concentration per unit cell in the absence of fluorescent dyes. The established method offered significantly enhanced selectivity compared to previously published procedures. In addition, this study demonstrates that a simple, quantitative targeted metabolomics approach can be developed to identify and quantify purine metabolites in biological samples. We envision that this method could be broadly applicable to quantification of purine metabolites from other complex biological samples, such as cerebrospinal fluid or blood.
Maternal immune activation causes age-specific changes in cytokine receptor expression in offspring throughout development
Authors: Estes Myka L. , Elmer Bradford M. , Carter Cameron C. , McAllister A. Kimberley
Published: December 2018

Maternal infection is a shared environmental risk factor for a spectrum of neuropsychiatric disorders and animal models of maternal immune activation (MIA) exhibit a range of neuropathologies and behaviors with relevance to these disorders. In particular, MIA offspring show chronic, age- and region-dependent changes in brain cytokines, a feature seen in postmortem studies of individuals with neuropsychiatric disorders. These MIA-induced alterations in brain cytokines may index biological processes underlying progression to diagnosable neuropsychiatric disorders. However, cytokines signal through specific cytokine receptors to alter cellular processes and it is the levels of those receptors that are critical for signaling. Yet, it remains unknown whether MIA alters the expression of cytokine receptors in the brains of offspring throughout postnatal development. Here, we measured the expression of 23 cytokine receptors in the frontal cortex of MIA and control offspring from birth to adulthood using qPCR. MIA offspring show dynamic oscillating alterations in cytokine receptors during sensitive periods of neural growth and synaptogenesis. Of the many cytokine receptors altered in the FC of MIA offspring, five were significantly changed at multiple ages at levels over 2-fold relative to controls (Il1r1, Ifngr1, Il10ra, Cx3cr1 and Gmcsfr), suggesting persistent dysfunction within those pathways. In addition to facilitating immune responses, these cytokine receptors play critical roles in neuronal migration and maturation, synapse formation and elimination, and microglial function. Together with previously reported changes in cytokine levels in the brains of MIA offspring, our results show a decrease in cytokine signaling during the peak period of synaptogenesis and spine formation and an increase during periods of activity-dependent developmentand early adulthood. Overall, the oscillating, age-dependent cytokine receptor alterations in the FC of MIA offspring identified here may have diagnostic and therapeutic value for neuropsychiatric disorders with a neuro-immune etiology.
Discovery of Alstrom syndrome gene as a regulator of centrosome duplication in asymmetrically dividing stem cells in Drosophila.: Supplementary table-mass spectrometry
Authors: Chen Cuie , Yamashita Yukiko
Published: December 2018

Stereotypical inheritance of the mother vs. daughter centrosomes has been reported in several stem cells that divide asymmetrically. We report the identification of a protein that exhibits asymmetric localization between mother and daughter centrosomes in asymmetrically dividing Drosophila male germline stem cells (GSCs). We show that Alms1a, a Drosophila homolog of the causative gene for the human ciliopathy Alstrom Syndrome, is a ubiquitous mother centriole protein with a unique additional localization to the daughter centriole only in the mother centrosome of GSCs. Depletion of alms1a results in rapid loss of centrosomes due to failure in daughter centriole duplication. We reveal that alms1a is specifically required for centriole duplication in asymmetrically dividing cells but not in symmetrically dividing differentiating cells in multiple stem cell lineages. The unique requirement of alms1a in asymmetric dividing cells may shed light onto the molecular mechanisms of Alstrom syndrome pathogenesis.
Spatial memory formation requires netrin-1 expression by neurons in the adult mammalian brain.
Authors: Wong Edwin , Glasgow Stephen D , Trigiani Lianne J , Chitsaz Daryan , Rymar Vladmir , Sadikot Abbas , Ruthazer Edward S , Hamel Edith , Kennedy Timothy E
Published: December 2018

Netrin-1 was initially characterized as an axon guidance molecule that is essential for normal embryonic neural development; however, many types of neurons continue to express netrin-1 in the post-natal and adult mammalian brain. Netrin-1 and the netrin receptor DCC are both enriched at synapses. In the adult hippocampus, activity-dependent secretion of netrin-1 by neurons potentiates glutamatergic synapse function, and is critical for long-term potentiation, an experimental cellular model of learning and memory. Here, we assessed the impact of neuronal expression of netrin-1 in the adult brain on behavior using tests of learning and memory. We show that adult mice exhibit impaired spatial memory following conditional deletion of netrin-1 from glutamatergic neurons in the hippocampus and neocortex. Further, we provide evidence that mice with conditional deletion of netrin-1 do not display aberrant anxiety-like phenotypes and show a reduction in self-grooming behaviour. These findings reveal a critical role for netrin-1 expressed by neurons in the regulation of spatial memory formation.
Multi-OMIC analysis of brain and serum from chronically-stressed mice reveals network disruptions in purine metabolism, fatty acid beta-oxidation, and antioxidant activity that are reversed by antidepressant treatment
Authors: Hamilton Peter J. , Chen Emily Y. , Tolstikov Vladimir , Peña Catherine J. , Shah Punit , Panagopoulos Kiki , Strat Ana N. , Walker Deena M. , Lorsch Zachary S. , Mervosh Nicholas L. , Kiraly Drew D. , Sarangarajan Rangaprasad , Narain Niven R. , Kiebish Michael A. , Nestler Eric J.
Published: December 2018

Major depressive disorder (MDD) is a complex condition with unclear pathophysiology. Molecular disruptions within the periphery and limbic brain regions contribute to depression symptomatology. Here, we utilized a mouse chronic stress model of MDD and performed metabolomic, lipidomic, and proteomic profiling on serum plus several brain regions (ventral hippocampus, nucleus accumbens, and prefrontal cortex) of susceptible, resilient, and unstressed control mice. Proteomic analysis identified three serum proteins reduced in susceptible animals; lipidomic analysis detected differences in lipid species between resilient and susceptible animals in serum and brain; and metabolomic analysis revealed pathway dysfunctions of purine metabolism, beta oxidation, and antioxidants, which were differentially associated with stress susceptibility vs resilience by brain region. Antidepressant treatment ameliorated MDD-like behaviors and affected key metabolites within outlined networks, most dramatically in the ventral hippocampus. This work presents a resource for chronic stress-induced, tissue-specific changes in proteins, lipids, and metabolites and illuminates how molecular dysfunctions contribute to individual differences in stress sensitivity.
Diversity of GABAergic interneurons and diversification of communication modules in cortical networks
Authors: Huang Z. Josh , Paul Anirban
Published: December 2018

The phenotypic diversity of cortical GABAergic neurons is likely necessary for their functional versatility in shaping exquisite spatiotemporal dynamics of circuit operations underlying cognitive processes. Deciphering the logic of this diversity requires overcoming the technical challenge of quantitative and comprehensive analysis of multi-modal cell features as well as the conceptual challenge of formulating a framework of neuronal identity that reflects biological mechanisms and principles. In the past few years, advances in high-throughput single cell analyses began to generate unprecedented datasets on interneuron transcriptomes, morphology and electrophysiology that drive their classification. Recent studies suggest that cardinal interneuron types can be defined by their synaptic communication properties encoded in key transcriptional signatures - a conceptual framework that integrates across phenotypic features and captures neuronal input-output properties elemental to circuit operation. This definition may further facilitate understanding the appropriate granularity of neuron types toward building a biologically-grounded and operationally useful interneuron taxonomy.
Domain topology, stability, and translation speed determine mechanical force generation on the ribosome
Authors: Leininge Sarah E. , Trovato Fabio , Nissley Daniel A. , O’Brien Edward P.
Published: December 2018

The concomitant folding of a nascent protein domain with its synthesis can generate mechanical forces that act on the ribosome and alter translation speed. Such changes in speed can affect the structure and function of the newly synthesized protein as well as cellular phenotype. The domain properties that govern force generation have yet to be identified and understood, and the influence of translation speed is unknown as all reported measurements have been carried out on arrested ribosomes. Here, using coarse-grained molecular simulations and statistical mechanical modeling of protein synthesis, we demonstrate that force generation is determined by a domain’s stability and topology, as well as translation speed. The statistical mechanical models we create predict how force profiles depend on these properties. These results indicate that force measurements on arrested ribosomes will not always accurately reflect what happens in a cell, especially for slow-folding domains, and suggest the possibility that certain domain properties may be enriched or depleted across the structural proteome of organisms through evolutionary selection pressures to modulate protein synthesis speed and post-translational protein behavior.

Significance Statement

Mechanochemistry, the influence of molecular-scale mechanical forces on chemical processes, can occur on actively translating ribosomes through the force-generating actions of motor proteins and the co-translational folding of domains. Such forces are transmitted to the ribosome’s catalytic core and alter rates of protein synthesis; representing a form of mechanical allosteric communication. These changes in translation-elongation kinetics are biologically important because they can influence protein structure, function, and localization within a cell. Many fundamental questions are unresolved concerning the properties of protein domains that determine mechanical force generation, the effect of translation speed on this force, and exactly how, at the molecular level, force is generated. In this study we answer these questions using cutting-edge molecular simulations and statistical mechanical modeling.
Salmonid gene expression biomarkers indicative of physiological responses to changes in salinity, temperature, but not dissolved oxygen
Authors: Houde Aimee Lee S. , Akbarzadeh Arash , Günther Oliver P. , Li Shaorong , Patterson David A. , Farrell Anthony P. , Hinch Scott G. , Miller Kristina M.
Published: December 2018

An organism’s ability to respond effectively to environmental change is critical to their survival. Yet, life stage and overall condition can dictate tolerance thresholds to heightened environmental stressors, such that stress may not be equally felt across individuals within a species. Environmental changes can induce transcriptional responses in an organism, some of which reflect generalized responses, and others are highly specific to the type of change being experienced. Thus, if transcriptional biomarkers specific to a heightened environmental stressor, even under multi-stressor impacts, can be identified, the biomarkers could be then applied in natural environments to determine when and where individuals are experiencing such stressors. Here, we validate candidate gill gene expression biomarkers by experimentally challenging juvenile Chinook salmon(Oncorhynchus tshawytscha). A sophisticated experimental set-up (four trials) manipulated salinity (freshwater, brackish water, and seawater), temperature (10, 14, and 18°C), and dissolved oxygen (normoxia and hypoxia), in all 18 possible combinations, for up to six days during the pre-smolt, smolt, and de-smolt life stages. In addition, we also describe the changes in juvenile behaviour, plasma variables, gill Na+/K+- ATPase (NKA) activity, body size, body morphology, and skin pigmentation associated with salinity, temperature, dissolved oxygen, mortality, and smolt status. We statistically identified biomarkers specific to salinity and temperature treatments, as well as mortality across multiple stressors and life stages. Similar biomarkers for the dissolved oxygen treatment could not be identified in the data and we discuss our next steps using an RNA-seq study. This work demonstrates the unique power of gene expression biomarkers to identify a specific stressor even under multi-stressor conditions.
“A Father and Mother More Worthy of Heaven Than of Earth”: The Promotion of the Cults of Louis and Zélie Martin by the Carmel of Lisieux, 1897–1959
Authors: Deboick Sophia L.
Published: December 2018

This article examines the promotion of the cults of the parents of Saint Thérèse of Lisieux by their daughters, nuns of the Carmel of Lisieux, from the time of Thérèse's death in 1897 until the late 1950s. Louis and Zélie Martin were made saints in the first joint canonisation of spouses in the history of the church in 2015 — this article traces the laying of the foundations for their official recognition well over half a century before. It examines in particular the work of Céline Martin (1869–1959), the chief promoter of Saint Thérèse's own cult and author of her popular image, in developing a public face for the Martin parents, situating this history within the interest of celebrity studies in the industrial production of celebrity. It goes on to analyse the modes in which the Martins were represented in both key images and texts — principally Céline's portraits of them and the biographies she wrote in the 1950s. It is shown that she ultimately wrote them into two devotional themes — that of sacrificial victimhood and abandonment to God's will — and in doing so cast them as precursors to Thérèse's own spiritual insights.
Prospective exosome‐focused translational research for afatinib study of non‐small cell lung cancer patients expressing EGFR (EXTRA study)
Authors: Okuma Yusuke , Morikawa Kei , Tanaka Hisashi , Yokoyama Takuma , Itani Hidetoshi , Horiuchi Kazuya , Nakagawa Hideyuki , Takahashi Nobumasa , Bessho Akihiro , Soejima Kenzo , Kishi Kazuma , Togashi Akira , Kanai Yae , Ueda Koji , Horimoto Katsuhisa , Matsutani Noriyuki , Seki Nobuhiko
Published: December 2018

Patients with EGFR‐mutated non‐small cell lung cancer (NSCLC) exhibit resistance to EGFR‐tyrosine kinase inhibitors (TKIs) within 9–14 months of therapy. Recently, EGFR‐mutated NSCLC has demonstrated the potential for heterogeneity; therefore, the manner of clonal heterogeneity may impact the duration of progression‐free and overall survival and other parameters affecting EGFR‐TKI treatment efficacy. However no predictive biomarker of these favorable treatment efficacies has been identified to date. The exosome‐focused translational research for afatinib (EXTRA) study aims to identify a novel predictive biomarker and a resistance marker for afatinib by analyzing data from association studies of the clinical efficacy of afatinib and four “OMICs” (genomics, proteomics, epigenomics, and metabolomics) using peripheral blood from patients treated with afatinib. This study aims to: (i) conduct comprehensive multi‐OMIC analyses in a prospective clinical trial, and (ii) focus on both sera/plasma and exosome as a source for OMIC analyses to identify a novel predictor of the efficacy of a specific drug. To eliminate the carryover bias of prior treatment, systemic treatment‐naïve patients were enrolled. The candidates to be screened for biomarkers comprise a discovery cohort of 60 patients and an independent validation cohort of 40 patients. The EXTRA study is the first trial to screen novel biomarkers of longer treatment efficacy of EGFR‐TKIs using four‐OMICs analyses, focusing on both “naked or free” molecules and “capsulated” exosomal components in serially collected peripheral blood.
Evaluating the performance of a deep learning‐based computer‐aided diagnosis (DL‐CAD) system for detecting and characterizing lung nodules: Comparison with the performance of double reading by radiologists
Authors: Li Li , Liu Zhou , Huang Hua , Lin Meng , Luo Dehong
Published: December 2018

Background

The study was conducted to evaluate the performance of a state‐of‐the‐art commercial deep learning‐based computer‐aided diagnosis (DL‐CAD) system for detecting and characterizing pulmonary nodules.

Methods

Pulmonary nodules in 346 healthy subjects (male: female = 221:125, mean age 51 years) from a lung cancer screening program conducted from March to November 2017 were screened using a DL‐CAD system and double reading independently, and their performance in nodule detection and characterization were evaluated. An expert panel combined the results of the DL‐CAD system and double reading as the reference standard.

Results

The DL‐CAD system showed a higher detection rate than double reading, regardless of nodule size (86.2% vs. 79.2%; P < 0.001): nodules ≥ 5 mm (96.5% vs. 88.0%; P = 0.008); nodules < 5 mm (84.3% vs. 77.5%; P < 0.001). However, the false positive rate (per computed tomography scan) of the DL‐CAD system (1.53, 529/346) was considerably higher than that of double reading (0.13, 44/346; P < 0.001). Regarding nodule characterization, the sensitivity and specificity of the DL‐CAD system for distinguishing solid nodules > 5 mm (90.3% and 100.0%, respectively) and ground‐glass nodules (100.0% and 96.1%, respectively) were close to that of double reading, but dropped to 55.5% and 93%, respectively, when discriminating part solid nodules.

Conclusion

Our DL‐CAD system detected significantly more nodules than double reading. In the future, false positive findings should be further reduced and characterization accuracy improved.