bluuebunny/crossref_metadata_2025 huggingface dataset:
Allele frequency-free inference of close familial relationships from genotypes or low depth sequencing data
Authors: Waples Ryan K , Albrechtsen Anders , Moltke Ida
Published: February 2018

Knowledge of how individuals are related is important in many areas of research and numerous methods for inferring pairwise relatedness from genetic data have been developed. However, the majority of these methods were not developed for situations where data is limited. Specifically, most methods rely on the availability of population allele frequencies, the relative genomic position of variants, and accurate genotype data. But in studies of non-model organisms or ancient human samples, such data is not always available. Motivated by this, we present a new method for pairwise relatedness inference, which requires neither allele frequency information nor information on genomic position. Furthermore, it can be applied to both genotype data and to low-depth sequencing data where genotypes cannot be accurately called. We evaluate it using data from SNP arrays and low-depth sequencing from a range of human populations and show that it can be used to infer close familial relationships with a similar accuracy as a widely used method that relies on population allele frequencies. Additionally, we show that our method is robust to SNP ascertainment, which is important for application to a diverse range of populations and species.
Proteomic analysis of chemosensory organs in the honey bee parasite Varroa destructor: a comprehensive examination of the potential carriers for semiochemicals
Authors: Iovinella Immacolata , McAfee Alison , Mastrobuoni Guido , Kempa Stefan , Foster Leonard J. , Pelosi Paolo , Dani Francesca Romana
Published: February 2018

The mite Varroa destructor is the major parasite of the honey bee and is responsible for great economical losses. The biochemical tools used by Varroa to detect semiochemicals produced by the host are still largely unknown. We have performed proteomic analysis on chemosensory organs of this species in order to identify putative soluble carriers for pheromones and other olfactory cues emitted by the host. In particular, we have analysed forelegs, mouthparts (palps, chelicera and hypostome) and the second pair of legs (as control tissue) in reproductive and phoretic stages of the Varroa life cycle. We identified 958 Varroa proteins, most of them common to organs and stages. Sequence analysis shows that four proteins can be assigned to the odorant-binding protein (OBP)-like class, which bear some similarity to insect OBPs, but so far are only reported in some Chelicerata. In addition, we have detected the presence of two proteins belonging to the Niemann-Pick family, type C2 (NPC2), which have been suggested to act as semiochemical carriers. This work contributes to elucidating the chemical communication systems in Varroa with the aim of understanding how detection of semiochemicals has evolved in terrestrial non-hexapod Arthropoda. Data are available via ProteomeXchange with identifier PXD008679.
Identification of parallel and divergent optimization solutions for homologous metabolic enzymes
Authors: Standaert Robert F. , Giannone Richard J. , Michener Joshua K.
Published: February 2018

Metabolic pathway assembly typically involves the expression of enzymes from multiple organisms in a single heterologous host. Ensuring that each enzyme functions effectively can be challenging, since many potential factors can disrupt proper pathway flux. These challenges are amplified when the enzymes are expressed at single copy from the chromosome. We have explored these issues using 4-hydroxybenzoate monooxygenase homologs heterologously expressed in Escherichia coli. Initial chromosomal enzyme expression was insufficient to support consistent growth with 4-hydroxybenzoate. Experimental evolution identified mutations that improved pathway activity. One set of mutations was common between homologs, while a second class of mutations was homolog-specific. Ultimately, we were able to identify a set of mutations that provided sufficient activity for growth with 4-hydroxybenzoate while maintaining or improving growth with protocatechuate. These findings demonstrate the potential for flexible, scalable chromosomal pathway engineering, as well as the value of directed evolution strategies to rapidly identify and overcome diverse factors limiting enzyme activity.
Long-read sequencing reveals the complex splicing profile of the psychiatric risk gene CACNA1C in human brain
Authors: Clark Michael B , Wrzesinski Tomasz , Garcia Aintzane B , Hall Nicola A. L. , Kleinman Joel E , Hyde Thomas , Weinberger Daniel R , Harrison Paul J , Haerty Wilfried , Tunbridge Elizabeth M
Published: February 2018

RNA splicing is a key mechanism linking genetic variation with psychiatric disorders. Splicing profiles are particularly diverse in brain and difficult to accurately identify and quantify. We developed a new approach to address this challenge, combining long-range PCR and nanopore sequencing with a novel bioinformatics pipeline. We identify the full-length coding transcripts of CACNA1C in human brain. CACNA1C is a psychiatric risk gene that encodes the voltage-gated calcium channel CaV1.2. We show that CACNA1C’s transcript profile is substantially more complex than appreciated, identifying 38 novel exons and 241 novel transcripts. Importantly, many of the novel variants are abundant, and predicted to encode channels with altered function. The splicing profile varies between brain regions, especially in cerebellum. We demonstrate that human transcript diversity (and thereby protein isoform diversity) remains under-characterised, and provide a feasible and cost-effective methodology to address this. A detailed understanding of isoform diversity will be essential for the translation of psychiatric genomic findings into pathophysiological insights and novel psychopharmacological targets.
A Chemical Biology Toolbox for the Study of Protein Methyltransferases and Epigenetic Signaling
Authors: Scheer Sebastian , Ackloo Suzanne , Medina Tiago S. , Schapira Matthieu , Li Fengling , Ward Jennifer A. , Lewis Andrew M. , Northrop Jeffrey P. , Richardson Paul L. , Kaniskan H. Ümit , Shen Yudao , Liu Jing , Smil David , Luo Minkui , Jin Jian , Barsyte-Lovejoy Dalia , Huber Kilian V. M. , De Carvalho Daniel D. , Vedadi Masoud , Zaph Colby , Brown Peter J. , Arrowsmith Cheryl H.
Published: February 2018

Protein methyltransferases (PMTs) comprise a major class of epigenetic regulatory enzymes with therapeutic relevance. Here we present a collection of chemical probes and associated reagents and data to elucidate the function of human and murine PMTs in cellular studies. Our collection provides inhibitors and antagonists that together modulate most of the key regulatory methylation marks on histones H3 and H4, providing an important resource for modulating cellular epigenomes. We describe a comprehensive and comparative characterization of the probe collection with respect to their potency, selectivity, and mode of inhibition. We demonstrate the utility of this collection in CD4+ T cell differentiation assays revealing the remarkable potential of individual probes to alter multiple T cell subpopulations with important implications for T cell-mediated processes such as inflammation and immuno-oncology. In particular, we demonstrate a role for DOT1L in limiting Th1 cell differentiation and maintaining lineage integrity.
RECAP reveals the true statistical significance of ChIP-seq peak calls
Authors: Chitpin Justin G. , Awdeh Aseel , Perkins Theodore J.
Published: February 2018

Motivation

ChlP-seq is used extensively to identify sites of transcription factor binding or regions of epigenetic modifications to the genome. A key step in ChIP-seq analysis is peak calling, where genomic regions enriched for ChIP versus control reads are identified. Many programs have been designed to solve this task, but nearly all fall into the statistical trap of using the data twice—once to determine candidate enriched regions, and again to assess enrichment by classical statistical hypothesis testing. This double use of the data invalidates the statistical significance assigned to enriched regions, and as a consequence, invalidates false discovery rate estimates. Thus, the true significance or reliability of peak calls remains unknown.

Results

Using simulated and real ChIP-seq data sets, we show that three well-known peak callers, MACS, SICER and diffReps, output optimistically biased p-values, and therefore optimistic false discovery rate estimates—in some cases, many orders of magnitude too optimistic. We propose a wrapper algorithm, RECAP, that uses resampling of ChIP-seq and control data to estimate and correct for biases built into peak calling algorithms. P-values recalibrated by RECAP are approximately uniformly distributed when applied to null hypothesis data, in which ChIP-seq and control come from the same genomic distributions. When applied to non-null data, RECAP p-values give a better estimate of the true statistical significance of candidate peaks and better false discovery rate estimates, which correlate better with empirical reproducibility. RECAP is a powerful new tool for assessing the true statistical significance of ChIP-seq peak calls.

Availability

The RECAP software is available on github at https://github.com/theodorejperkins/RECAP.

Contact

tperkins@ohri.ca
Increased autophagy in ephrinB2 deficient osteocytes is associated with hypermineralized, brittle bones
Authors: Vrahnas Christina , Dite Toby A , Ansari Niloufar , Crimeen-Irwin Blessing , Nguyen Huynh , Forwood Mark R , Hu Yifang , Ikegame Mika , Bambery Keith R , Petibois Cyril , Tobin Mark J , Smyth Gordon K , Oakhill Jonathan S , Martin T John , Sims Natalie A
Published: February 2018

Mineralized bone forms when collagen-containing osteoid accrues hydroxyapatite crystals. This process has two phases: a rapid initiation (primary mineralization), followed by slower accrual of mineral (secondary mineralization) that continues until that portion of bone is renewed by remodelling. Within the bone matrix is an interconnected network of cells termed osteocytes. These cells are derived from bone-forming osteoblasts. Osteoblast differentiation requires expression of ephrinB2, and we were intrigued about why ephrinB2 continues to be expressed in mature osteocytes. To determine its function in osteocytes, we developed an osteocyte-specific ephrinB2 null mouse and found they exhibited a brittle bone phenotype. This was not caused by a change in bone mass, but by an intrinsic defect in the strength of the bone material. Although the initiation of osteoid mineralization occurred at a normal rate, the process of secondary mineralization was accelerated in these mice. The maturing mineralized bone matrix incorporated mineral and carbonate more rapidly than controls, indicating that osteocytic ephrinB2 suppresses mineral accumulation in bone. No known regulators of mineralization were modified in the bone of these mice. However, RNA sequencing showed differential expression of a group of autophagy-associated genes, and increased autophagic flux was confirmed in ephrinB2 knockdown osteocytes. This indicates that the process of secondary mineralization in bone makes use of autophagic machinery in a manner that is limited by ephrinB2 in osteocytes, and that this process may be disrupted in conditions of bone fragility.
PSF correction in soft x-ray tomography
Authors: Ekman Axel , Weinhardt Venera , Chen Jian-Hua , McDermott Gerry , Le Gros Mark A. , Larabell Carolyn
Published: February 2018

In this manuscript, we introduce a linear approximation of the forward model of soft x-ray tomography (SXT), such that the reconstruction is solvable by standard iterative schemes. This linear model takes into account the three-dimensional point spread function (PSF) of the optical system, which consequently enhances the reconstruction data. The feasibility of the model is demonstrated on both simulated and experimental data, based on theoretically estimated and experimentally measured PSFs.
Theta bursts precede, and spindles follow, cortical and thalamic downstates in human NREM sleep
Authors: Gonzalez Chris , Mak-McCully Rachel , Rosen Burke , Cash Sydney S. , Chauvel Patrick , Bastuji Hélène , Rey Marc , Halgren Eric
Published: February 2018

Since their discovery, slow oscillations have been observed to group spindles during non-REM sleep. Previous studies assert that the slow oscillation downstate (DS) is preceded by slow spindles (10-12Hz), and followed by fast spindles (12-16Hz). Here, using both direct transcortical recordings in patients with intractable epilepsy (n=10, 8 female), as well as scalp EEG recordings from a healthy cohort (n=3, 1 female), we find in multiple cortical areas that both slow and fast spindles follow the DS. Although discrete oscillations do precede DSs, they are theta bursts (TB) centered at 5-8Hz. TBs were more pronounced for DSs in NREM stage N2 compared with N3. TB with similar properties occur in the thalamus, but unlike spindles they have no clear temporal relationship with cortical TB. These differences in corticothalamic dynamics, as well as differences between spindles and theta in coupling high frequency content, are consistent with NREM theta having separate generative mechanisms from spindles. The final inhibitory cycle of the TB coincides with the DS peak, suggesting that in N2, TB may help trigger the DS. Since the transition to N1 is marked by the appearance of theta, and the transition to N2 by the appearance of DS and thus spindles, a role of TB in triggering DS could help explain the sequence of electrophysiological events characterizing sleep. Finally, the coordinated appearance of spindles and DSs are implicated in memory consolidation processes, and the current findings redefine their temporal coupling with theta during NREM sleep.

Significance Statement

Sleep is characterized by large slow waves which modulate brain activity. Prominent among these are ‘downstates,’ periods of a few tenths of a second when most cells stop firing, and ‘spindles,’ oscillations at about twelve times a second lasting for about a second. In this study, we provide the first detailed description of another kind of sleep wave: ‘theta bursts,’ a brief oscillation at about six cycles per second. We show, recording during natural sleep directly from the human cortex and thalamus, as well as on the human scalp, that theta bursts precede, and spindles follow downstates. Theta bursts may help trigger downstates in some circumstances, and organize cortical and thalamic activity so that memories can be consolidated during sleep.
ChIP-BIT2: a software tool to detect weak binding events using a Bayesian integration approach
Authors: Chen Xi , Shi Xu , Hilakivi-Clarke Leena , Clarke Robert , Wang Tian-Li , Xuan Jianhua
Published: February 2018

Transcription factor binding events play important functional roles in gene regulation. It is, however, a challenging task to detect weak binding events since the ambiguity in differentiation of weak binding signals from background signals. We present a software package, ChIP-BIT2, to identify weak binding events using a Bayesian integration approach. By integrating signals from sample and input ChIP-seq data, ChIP-BIT2 can detect both strong and weak binding events at gene promoter, enhancer or the whole genome effectively. The ChIP-BIT2 package has been extensively tested on ChIP-seq data, demonstrating its wide applicability in ChIP-seq data analysis.

Availability and Implementation

The ChIP-BIT2 package is available at http://sourceforge.net/projects/chipbitc/.
DPP9 is an endogenous and direct inhibitor of the NLRP1 inflammasome that guards against human auto-inflammatory diseases
Authors: Zhong Franklin L. , Robinson Kim , Lim Chrissie , Harapas Cassandra R. , Yu Chien-Hsiung , Xie William , Sobota Radoslaw M. , Bijin Au Veonice , Hopkins Richard , Connolly John E. , Masters Seth , Reversade Bruno
Published: February 2018

The inflammasome is a critical immune complex that activates IL-1 driven inflammation in response to pathogen- and danger-associated signals. Nod-like receptor protein-1 (NLRP1) is a widely expressed inflammasome sensor. Inherited gain-of-function mutations in NLRP1 cause a spectrum of human Mendelian diseases, including systemic autoimmunity and skin cancer susceptibility. However, its endogenous regulation and its cognate ligands are still unknown. Here we apply a proteomics screen to identify dipeptidyl dipeptidase, DPP9 as a novel interacting partner and a specific endogenous inhibitor of NLRP1 inflammasome in diverse primary cell types from human and mice. DPP9 inhibition via small molecule drugs, targeted mutations in its catalytic site and CRISPR/Cas9-mediated genetic deletion potently and specifically activate the NLRP1 inflammasome leading to pyroptosis and IL-1 processing via ASC and caspase-1. Mechanistically, DPP9 maintains NLRP1 in its monomeric, inactive state by binding to the auto-cleaving FIIND domain. NLRP1-FIIND is a self-sufficient DPP9 binding module and its disruption by a single missense mutation abrogates DPP9 binding and explains the aberrant inflammasome activation in NAIAD patients with arthritis and dyskeratosis. These findings uncover a unique peptidase enzyme-based mechanism of inflammasome regulation, and suggest that the DPP9-NLRP1 complex could be broadly involved in human inflammatory disorders.
A conserved regulatory program drives emergence of the lateral plate mesoderm
Authors: Prummel Karin D. , Hess Christopher , Nieuwenhuize Susan , Parker Hugo J. , Rogers Katherine W. , Kozmikova Iryna , Racioppi Claudia , Brombacher Eline C. , Czarkwiani Anna , Knapp Dunja , Burger Sibylle , Chiavacci Elena , Shah Gopi , Burger Alexa , Huisken Jan , Yun Maximina H. , Christiaen Lionel , Kozmik Zbynek , Müller Patrick , Bronner Marianne , Krumlauf Robb , Mosimann Christian
Published: February 2018

Cardiovascular lineages develop together with kidney, smooth muscle, and limb connective tissue progenitors from the lateral plate mesoderm (LPM). How the LPM initially emerges and how its downstream fates are molecularly interconnected remain unknown. Here, we isolated a pan-LPM enhancer in the zebrafishdraculin(drl) gene that provides specific LPM reporter activity from early gastrulation.In totolive imaging and lineage tracing ofdrl-based reporters captured the dynamic LPM emergence as lineage-restricted mesendoderm field. Thedrlpan-LPM enhancer responds to the transcription factors EomesoderminA, FoxH1, and MixL1 that combined with Smad activity drive LPM emergence. We uncovered specificdrlreporter activity in LPM-corresponding territories of several chordates including chicken, axolotl, lamprey,Ciona, and amphioxus, revealing a universal upstream LPM program. Altogether, our work provides a mechanistic framework for LPM emergence as defined progenitor field, possibly representing an ancient mesodermal cell state that predates the primordial vertebrate embryo.
Integrating Hi-C links with assembly graphs for chromosome-scale assembly
Authors: Ghurye Jay , Rhie Arang , Walenz Brian P. , Schmitt Anthony , Selvaraj Siddarth , Pop Mihai , Phillippy Adam M. , Koren Sergey
Published: February 2018

Long-read sequencing and novel long-range assays have revolutionizedde novogenome assembly by automating the reconstruction of reference-quality genomes. In particular, Hi-C sequencing is becoming an economical method for generating chromosome-scale scaffolds. Despite its increasing popularity, there are limited open-source tools available. Errors, particularly inversions and fusions across chromosomes, remain higher than alternate scaffolding technologies. We present a novel open-source Hi-C scaffolder that does not require ana prioriestimate of chromosome number and minimizes errors by scaffolding with the assistance of an assembly graph. We demonstrate higher accuracy than the state-of-the-art methods across a variety of Hi-C library preparations and input assembly sizes. The Python and C++ code for our method is openly available athttps://github.com/machinegun/SALSA

Author summary

Hi-C technology was originally proposed to study the 3D organization of a genome. Recently, it has also been applied to assemble large eukaryotic genomes into chromosome-scale scaffolds. Despite this, there are few open source methods to generate these assemblies. Existing methods are also prone to small inversion errors due to noise in the Hi-C data. In this work, we address these challenges and develop a method, named SALSA2. SALSA2 uses sequence overlap information from an assembly graph to correct inversion errors and provide accurate chromosome-scale assemblies.
Optimizing Trait Predictability in Hybrid Rice Using Superior Prediction Models and Selective Omic Datasets
Authors: Wang Shibo , Wei Julong , Li Ruidong , Qu Han , Xie Weibo , Jia Zhenyu
Published: February 2018

Hybrid breeding has dramatically boosted yield and its stability in rice. Genomic prediction further benefits rice breeding by increasing selection intensity and accelerating breeding cycles. With the rapid advancement of technology, other omic data, such as metabolomic data and transcriptomic data, are readily available for predicting genetic values (or breeding values) for agronomically important traits. In the current study, we searched for the best prediction strategy for four traits (yield, 1000 grain weight, number of grains per panicle and number of tillers per plant) of hybrid rice by evaluating all possible combinations of omic datasets with different prediction methods. We conclude that, in rice, the predictions using the combination of genomic and metabolomic data generally produce better results than single-omics predictions or predictions based on other combined omic data. Inclusion of transcriptomic data does not improve predictability possibly because transcriptome does not provide more information for the trait than the sum of genome and metabolome; rather, the computational complexity is substantially increased if transcriptomic data is included in the models. Best linear unbiased prediction (BLUP) appears to be the most efficient prediction method compared to the other commonly used approaches, including LASSO, SSVS, SVM-RBF, SVP-POLY and PLS. Our study has provided a guideline for selection of hybrid rice in terms of which types of omic datasets and which method should be used to achieve higher trait predictability.
Non-Canonical Activation of CREB Mediates Neuroprotection in aC. elegansModel of Excitotoxic Necrosis
Authors: Feldmann K. Genevieve , Chowdhury Ayesha , Becker Jessi , McAlpin N’Gina , Ahmed Taqwa , Haider Syed , Xia Jian X. Richard , Diaz Karina , Mehta Monal G. , Mano Itzhak
Published: February 2018

Excitotoxicity, caused by exaggerated neuronal stimulation by Glutamate (Glu), is a major cause of neurodegeneration in brain ischemia. While we know that neurodegeneration is triggered by overstimulation of Glu-Receptors (GluRs), the subsequent mechanisms that lead to cellular demise remain controversial. Surprisingly, signaling downstream of GluRs can also activate neuroprotective pathways. The strongest evidence involves activation of the transcription factor cAMP Response Element Binding-protein (CREB), widely recognized for its importance in synaptic plasticity. Canonical views describe CREB as a phosphorylation-triggered transcription factor, where transcriptional activation involves CREB phosphorylation and association with CREB Binding Protein (CBP). However, given CREB’s ubiquitous cross-tissue expression, the multitude of cascades leading to CREB phosphorylation, and its ability to regulate thousands of genes, it remains unclear how CREB exerts closely-tailored, differential neuroprotective responses in excitotoxicity. A non-canonical, alternative cascade for activation of CREB-mediated transcription involves the CREB co-factor cAMP-regulated transcriptional co-activator (CRTC), and may be independent of CREB phosphorylation. To identify cascades that activate CREB in excitotoxicity we use aC. elegansmodel of neurodegeneration by excitotoxic necrosis. We demonstrate that CREB’s neuroprotective effect is conserved, and seems most effective in neurons with moderate Glu exposure. We find that factors mediating canonical CREB activation are not involved. Instead, phosphorylation-independent CREB activation in nematode excitotoxic necrosis hinges on CRTC. CREB-mediated transcription that depends on CRTC, but not on CREB phosphorylation, might lead to expression of a specific subset of neuroprotective genes. Elucidating conserved mechanisms of excitotoxicity-specific CREB activation can help us focus on core neuroprotective programs in excitotoxicity.
Generation of pulmonary neuro-endocrine cells and tumors resembling small cell lung cancers from human embryonic stem cells
Authors: Chen Huanhuan Joyce , Poran Asaf , Unni Arun M. , Huang Sarah Xuelian , Elemento Olivier , Snoeck Hans-Willem , Varmus Harold
Published: February 2018

By blocking an important signaling pathway (called NOTCH) and interfering with expression of two tumor suppressor genes in cells derived from human embryonic stem cells, the authors have developed a model for studying highly lethal small cell lung cancers.

Cell culture models based on directed differentiation of human embryonic stem cells (hESCs) may reveal why certain constellations of genetic changes drive carcinogenesis in specialized human cell lineages. Here we demonstrate that up to 10 percent of lung progenitor cells derived from hESCs can be induced to form pulmonary neuroendocrine cells (PNECs), the putative normal precursors to small cell lung cancers (SCLCs), by inhibition of NOTCH signaling. By using small inhibitory RNAs in these cultures to reduce levels of retinoblastoma (RB) protein, the product of a gene commonly mutated in SCLCs, we can significantly expand the number of PNECs. Similarly reducing levels of TP53 protein, the product of another tumor suppressor gene commonly mutated in SCLCs, or expressing mutantKRASorEGFRgenes, did not induce or expand PNECs, consistent with lineage-specific sensitivity to loss ofRBfunction. Tumors resembling early stage SCLC grew in immunodeficient mice after subcutaneous injection of PNEC-containing cultures in which expression of bothRBandTP53was blocked. Single-cell RNA profiles of PNECs are heterogeneous; when RB levels are reduced, the profiles show similarities to RNA profiles from early stage SCLC; when both RB and TP53 levels are reduced, the transcriptome is enriched with cell cycle-specific RNAs. Taken together, these findings suggest that genetic manipulation of hESC-derived pulmonary cells will enable studies of the initiation, progression, and treatment of this recalcitrant cancer.
Adaptation to sub-optimal hosts is a driver of viral diversification in the ocean
Authors: Enav Hagay , Kirzner Shay , Lindell Debbie , Mandel-Gutfreund Yael , Béjà Oded
Published: February 2018

Marine cyanophages are viruses that infect oceanic cyanobacteria, thus affecting global ecological processes. Cyanophages of theMyoviridaefamily are of great interest since they include generalist viruses capable of infection of a wide range of hosts including those from different cyanobacterial genera. While the influence of phages on host evolution has been studied previously, it is not known how the infection of distinct hosts influences the evolution of cyanophage populations. In marine systems this question is of special interest as the abundance of differentSynechococcusandProchlorococcushosts constantly changes, temporally and spatially. Here, using an experimental evolution approach, we investigated the adaptation of multiple cyanophage populations to three distinct cyanobacterial hosts. We show that when infecting an “optimal” host, whose infection is the most efficient, phage populations accumulated only a few mutations. However, when infecting “sub-optimal” hosts, different, largely host-specific sets of mutations, spread in the phage populations, leading to rapid diversification into distinct subpopulations. The mutations included insertions, deletions, SNPs and codon adaptations. Most of the mutations were found in genes encoding for proteins responsible for host recognition, attachment and infection, regardless of their evolutionary conservation. Based on our results, we propose a model demonstrating how shifts in bacterial abundance, which lead to infection of “sub-optimal” hosts, act as a driver for rapid diversification of phage populations.
Single-trial Phase Entrainment of Theta Oscillations in Sensory Regions Predicts Human Associative Memory Performance
Authors: Wang Danying , Clouter Andrew , Chen Qiaoyu , Shapiro Kimron L. , Hanslmayr Simon
Published: February 2018

Episodic memories are rich in sensory information and often contain integrated information from different sensory modalities. For instance, we can store memories of a recent concert with visual and auditory impressions being integrated in one episode. Theta oscillations have recently been implicated in playing a causal role synchronizing and effectively binding the different modalities together in memory. However, an open question is whether momentary fluctuations in theta synchronization predict the likelihood of associative memory formation for multisensory events. To address this question we presented movies and sounds with their luminance and volume modulated at theta (4 Hz), with a phase offset at 0° or 180° with respect to each other. This allowed us to entrain the visual and auditory cortex in a synchronous (0°) or asynchronous manner (180°). Participants were asked to remember the association between a movie and a sound while having their EEG activity recorded. Associative memory performance was significantly enhanced in the synchronous (0°) compared to the asynchronous (180°) condition. Source-level analysis demonstrated that the physical stimuli effectively entrained their respective cortical areas with a corresponding phase offset. Importantly, the strength of entrainment during encoding correlated with the efficacy of associative memory such that small phase differences between visual and auditory cortex predicted a high likelihood of correct retrieval in a later recall test. These findings suggest that theta oscillations serve a specific function in the episodic memory system: Binding the contents of different modalities into coherent memory episodes.

Significance Statement

How multi-sensory experiences are bound to form a coherent episodic memory representation is one of the fundamental questions in human episodic memory research. Evidence from animal literature suggests that the relative timing between an input and theta oscillations in the hippocampus is crucial for memory formation. We precisely controlled the timing between visual and auditory stimuli and the neural oscillations at 4 Hz using a multisensory entrainment paradigm. Human associative memory formation depends on coincident timing between sensory streams processed by the corresponding brain regions. We provide evidence for a significant role of relative timing of neural theta activity in human episodic memory on a single trial level, which reveals a crucial mechanism underlying human episodic memory.
In situ relationships between microbiota and potential pathobiota in Arabidopsis thaliana
Authors: Bartoli Claudia , Frachon Léa , Barret Matthieu , Rigal Mylène , Huard-Chauveau Carine , Mayjonade Baptiste , Zanchetta Catherine , Bouchez Olivier , Roby Dominique , Carrère Sébastien , Roux Fabrice
Published: February 2018

A current challenge in microbial pathogenesis is to identify biological control agents that may prevent and/or limit host invasion by microbial pathogens. In natura, hosts are often infected by multiple pathogens. However, most of the current studies have been performed under laboratory controlled conditions and by taking into account the interaction between a single commensal species and a single pathogenic species. The next step is therefore to explore the relationships between host-microbial communities (microbiota) and microbial members with potential pathogenic behavior (pathobiota) in a realistic ecological context. In the present study, we investigated such relationships within root and leaf associated bacterial communities of 163 ecologically contrasted Arabidopsis thaliana populations sampled across two seasons in South-West of France. In agreement with the theory of the invasion paradox, we observed a significant humped-back relationship between microbiota and pathobiota α-diversity that was robust between both seasons and plant organs. In most populations, we also observed a strong dynamics of microbiota composition between seasons. Accordingly, the potential pathobiota composition was explained by combinations of season-specific microbiota OTUs. This result suggests that the potential biomarkers controlling pathogen’s invasion are highly dynamic.
Silencing of a unique integrated domain nucleotide-binding leucine-rich repeat gene in wheat abolishesDiuraphis noxiaresistance
Authors: Nicolis Vittorio , Venter Eduard
Published: February 2018

Plants respond in a similar manner to aphid feeding as to pathogen attack.Diuraphis noxiais a specialist aphid, feeding only on selected grasses that include wheat, barley, and oats. The wheat-Diuraphis noxiainteraction is characterized by very similar responses as seen in wheat-pathogen interactions with none of the underlying resistance pathways and genes characterized yet. From wheat harboring theDn1resistance gene, we have identified a nucleotide-binding leucine-rich repeat (NLR) gene containing two integrated domains (IDs). These are three C-terminus ankyrin repeat-domains and an N-terminus WRKY domain. The NLR core of the gene can be traced through speciation events within the grass family, with a recent WRKY domain integration that isTriticumspecific. Virus induced gene silencing of the gene in resistant wheat lines resulted in the abolishment of localized cell death. Silenced plants supported a higher number of aphids similar to the susceptible NIL and the intrinsic rate of increase of the aphids matched that of aphids feeding on the susceptible NIL. The presence of the gene is necessary forDn1resistance and we have named the geneAssociated with Dn resistance 1(Adr1) to reflect this function.
Hair cells with heterogeneous transfer characteristics encode mechanical stimuli in the lateral line of zebrafish
Authors: Pichler Paul , Lagnado Leon
Published: February 2018

Ribbon synapses of hair cells transmit mechanical information but the transfer characteristics relating deflection of the hair bundle to glutamate release have not been assessed directly. Here we have imaged glutamate to investigate how hair cells encode information in the lateral line of zebrafish. Half the hair cells signalled cupula motion in either direction from rest, achieving maximum sensitivity for deflections of ~40 nm in the preferred direction. The remainder rectified completely and were less sensitive, extending the operating range of the neuromast beyond 1μm. Adaptation was also heterogeneous, with some hair cells generating sustained synaptic outputs and others transient. A unique signal encoded a return to rest: a transient burst from hair cells unresponsive to the initial stimulus. A mixed population of hair cells with these various transfer characteristics will allow a neuromast to encode weak stimuli as well as the amplitude and duration of stronger deflections.
FGF activity asymmetrically regulates the timing of habenular neurogenesis in a Nodal-dependent manner
Authors: Dean Benjamin J. , Gamse Joshua T. , Wu Shu-Yu
Published: February 2018

The highly conserved habenular nuclei in the vertebrate epithalamus function as an integrating center that relaying information between the forebrain and the brain stem. These nuclei play crucial roles in modulating a broad variety of cognitive behaviors. Moreover, habenular nuclei has also attracted interest as a model for brain asymmetry, since many vertebrates exhibit left-right differences in habenular size and neural circuitry. Left-right (L/R) asymmetry is a shared feature of the central nervous system in vertebrates. Despite its prevalence and functional significance, few studies have addressed the molecular bases for the generation of the asymmetric brain structure, perhaps due to the absence of genetically accessible model animals showing robust brain asymmetry. Previous studies on zebrafish epithalamus demonstrated that Nodal signaling directs the habenular asymmetry during the early stages of development by biasing the neurogenesis on the left-side. Here, we discover a novel regulatory module involving asymmetric activation of FGF signaling that determines the timing of habenular neurogenesis by regulating cell-cycle progression of neuronal progenitors, which seamlessly integrates the L/R patterning driven by Nodal and the spatiotemporal patterning of habenular neurons.
Co-entangled actin-microtubule composites exhibit tunable stiffening and power-law stress relaxation
Authors: Ricketts Shea N. , Ross Jennifer L. , Robertson-Anderson Rae M.
Published: February 2018

We use optical tweezers microrheology and fluorescence microscopy to characterize the nonlinear mesoscale mechanics and mobility of in vitro co-entangled actin-microtubule composites. We create a suite of randomly-oriented, well-mixed networks of actin and microtubules by co-polymerizing varying ratios of actin and tubulin in situ. To perturb each composite far from equilibrium, we use optical tweezers to displace an embedded microsphere a distance greater than the lengths of the filaments at a speed much faster than their intrinsic relaxation rates. We simultaneously measure the resistive force the filaments exert and the subsequent force relaxation. We find that the presence of a large fraction of microtubules (>0.7) is needed to substantially increase the resistive force, which is accompanied by large heterogeneities in force response. Actin minimizes these heterogeneities by reducing the mesh size of the composites and supporting microtubules against buckling. Composites also undergo a sharp transition from stress-softening to stiffening when the fraction of microtubules (ϕT) exceeds 0.5, by microtubules suppressing actin bending fluctuations. The induced force following strain relaxes via two time-dependent power-law decays. The first decay phase, with scaling exponents that increase proportionally with the fraction of actin, signifies actin bending fluctuations. Alternatively, the second phase, with a ϕT-independent scaling exponent of ~0.4, is indicative of filaments reptating out of deformed entanglement constraints. Corresponding mobility measurements of steady-state actin and microtubules show that both filaments are more mobile in equimolar composites (ϕT=0.5) compared to networks of primarily actin or microtubules. This non-monotonic dependence of mobility on ϕT, which further demonstrates the important role mesh size plays in composites, highlights the surprising emergent properties that can arise in composites.
Identification of piRNA binding sites reveals the Argonaute regulatory landscape of theC. elegansgermline
Authors: Shen En-Zhi , Chen Hao , Ozturk Ahmet R. , Tu Shikui , Shirayama Masaki , Tang Wen , Ding Yue-He , Dai Si-Yuan , Weng Zhiping , Mello Craig C.
Published: February 2018

piRNAs (Piwi-interacting small RNAs) engage Piwi Argonautes to silence transposons and promote fertility in animal germlines. Genetic and computational studies have suggested thatC. eleganspiRNAs tolerate mismatched pairing and in principle could target every transcript. Here we employin vivocross-linking to identify transcriptome-wide interactions between piRNAs and target RNAs. We show that piRNAs engage all germline mRNAs and that piRNA binding follows microRNA-like pairing rules. Targeting correlates better with binding energy than with piRNA abundance, suggesting that piRNA concentration does not limit targeting. In mRNAs silenced by piRNAs, secondary small RNAs accumulate at the center and ends of piRNA binding sites. In germline-expressed mRNAs, however, targeting by the CSR-1 Argonaute correlates with reduced piRNA binding density and suppression of piRNA-associated secondary small RNAs. Our findings reveal physiologically important and nuanced regulation of individual piRNA targets and provide evidence for a comprehensive post transcriptional regulatory step in germline gene expression.
Xrn2 accelerates termination by RNA polymerase II, which is underpinned by CPSF73 activity
Authors: Eaton Joshua D. , Davidson Lee , Bauer David L.V. , Natsume Toyoaki , Kanemaki Masato T. , West Steven
Published: February 2018

Termination is a ubiquitous phase in every transcription cycle but is incompletely understood and a subject of debate. We used gene editing as a new approach to address its mechanism through engineered conditional depletion of the 5′ → 3′ exonuclease Xrn2 or the polyadenylation signal (PAS) endonuclease CPSF73 (cleavage and polyadenylation specificity factor 73). The ability to rapidly control Xrn2 reveals a clear and general role for it in cotranscriptional degradation of 3′ flanking region RNA and transcriptional termination. This defect is characterized genome-wide at high resolution using mammalian native elongating transcript sequencing (mNET-seq). An Xrn2 effect on termination requires prior RNA cleavage, and we provide evidence for this by showing that catalytically inactive CPSF73 cannot restore termination to cells lacking functional CPSF73. Notably, Xrn2 plays no significant role in either Histone or small nuclear RNA (snRNA) gene termination even though both RNA classes undergo 3′ end cleavage. In sum, efficient termination on most protein-coding genes involves CPSF73-mediated RNA cleavage and cotranscriptional degradation of polymerase-associated RNA by Xrn2. However, as CPSF73 loss caused more extensive readthrough transcription than Xrn2 elimination, it likely plays a more underpinning role in termination.
Does hedging enhance firm value in good and bad times
Authors: Alam Nafis , Gupta Amit
Published: February 2018

Purpose

The purpose of this paper is to examine if the hedging strategy of the firm adds value to the firm, and if so, is the source of the benefit consistent with the hedging theory?

Design/methodology/approach

The paper used data from 129 top non-financial Indian companies spanning a period of 2008-2015 and analyzed using the ordinary least squares regression technique.

Findings

The study finds that firms engaged in hedging compared to non-hedgers have less volatility in the firm’s value. The use of hedging during the financial crisis is found to be value enhancing for the hedgers. The results also found that some firms do not disclose the notional value of derivatives clearly, which highlights the need of clear regulation for derivative declaration in the annual reports.

Research limitations/implications

Research implications of this study are to gain an insight into the hedging effectiveness in the highly volatile Indian market as compared to developed countries. High volatility in the exchange rate of Indian rupee further makes it one of the most relevant markets to study the effect of hedging on the firm’s value.

Practical implications

Mostly hedging is done purely for risk management, and if managers try to time the market by selective hedging, it can bring a negative impact for the firm. Findings show that managers should manage their hedging strategy based on changing the economic environment and not purely on the firms’ financial value.

Originality/value

To the authors’ best knowledge, this is the first study to extract the dollar value of derivative usage of sample firms and analyze its effectiveness in enhancing firm value in the presence of other financial parameters. This will be an advancement of previous studies, which used hedging as a dummy variable only. Most studies on this topic are carried out in developed countries; there is a limited research on developing markets such as India, and past studies have been more generic one like determinants of hedging and overall derivative scenario.
Audit committee adoption and firm value: evidence from UK financial institutions
Authors: Agyemang-Mintah Peter , Schadewitz Hannu
Published: February 2018

Purpose

This paper aims to examine the impact of audit committee (AC) adoption on the financial value of financial institutions in the UK and also to examine the impact of the establishment of an AC on firm value during the pre/post-global financial crisis era.

Design/methodology/approach

The paper embarks on a theoretical and empirical literature review on AC adoption and its impact on a firm’s financial value. The paper uses data from 63 financial institutions and covers a 12-year period.

Findings

The empirical results indicate that the adoption of an AC by financial institutions has a positive and statistically significant impact on firm value. The results from the pre-crisis period also indicate that the adoption of an AC makes a positive and significant contribution to firm value. However, there is no impact on firm value during the post-crisis period. The results suggest that the entire UK economy experienced an economic downturn after the financial crisis (2009-2011), and financial firms were no exception.

Research limitations/implications

This study helps to fill research gaps on the relationships between ACs and firm value as they exist in UK financial institutions. These findings are important for policymakers and regulators.

Practical implications

This research will encourage firms to establish ACs.

Social implications

This new finding about the importance of firms having an AC in place is important for policymakers and regulators.

Originality/value

To the best of the authors’ knowledge, this research is the first to conduct an empirical study of the effect of AC adoption on UK financial institutions and firm value. Second, no single study has been conducted on the effects of AC adoption and its impact on either the pre- or post-financial crisis periods. This is the first paper to provide such empirical evidence.
Mandatory IFRS adoption, investor protection and earnings management
Authors: Kouki Ahmed
Published: February 2018

Purpose

The purpose of this paper is to examine the effect of investor protection on earnings management before and after IFRS adoption.

Design/methodology/approach

A sample of 106 companies listed on Germany, France and Belgium stock markets for the pre-IFRS (2000-2004) and post-IFRS (2006-2011) periods was used. This research is based on a comparative study between the pre- and the post-IFRS periods.

Findings

The results showed that investor protection better explains earnings management after the transition to IFRS. The findings revealed that international standards and investor protection are significant in jointly explaining earnings management for the second reporting period.

Originality/value

The study gives rise to a score that is considered as a proxy of investor protection that regroups several macroeconomic indexes.