bluuebunny/crossref_metadata_2025 huggingface dataset:
Minimum requirements for reprogramming and maintaining cell fate in theArabidopsisroot
Authors: Drapek Colleen , Sparks Erin E. , Marhavy Peter , Andersen Tonni G. , Hennacy Jessica H. , Geldner Niko , Benfey Philip N.
Published: November 2017

Changes in gene regulation during differentiation are governed by networks of transcription factors. To identify the minimal network for endodermal differentiation in theArabidopsisroot, we asked what transcription factors are sufficient to program a non-native cell-type into endodermis. Our results show the transcription factors SHORTROOT and MYB36 have limited ability to reprogram a non-native cell-type (the epidermis) and that this reprogramming is reversible in the absence of additional cues. The stele-derived signaling peptide CIF2 stabilizes SHORTROOT-induced reprogramming. The outcome is a partially impermeable barrier deposited in the sub-epidermal cell layer that has a transcriptional signature similar to endodermis. The trans-differentiation mechanism depends on the expression of genes downstream in the gene regulatory network but is independent of SHORTROOT movement. These results highlight a non cell-autonomous induction mechanism for endodermis that resembles differentiation in many animal systems.

One Sentence Summary

SHORTROOT and CIF2 combined can induce and stabilize an endodermis in sub-epidermal cells and do so in a non cell-autonomous manner.
Anterior temporal lobe morphometry predicts categorization ability
Authors: Garcin B. , Urbanski M. , Schotten M. Thiebaut De , Levy R. , Volle E.
Published: November 2017

Categorization is the mental operation by which the brain classifies objects and events. It is classically assessed using semantic and non-semantic matching or sorting tasks. These tasks show a high variability in performance across healthy controls and the cerebral bases supporting this variability remain unknown. In this study we performed a voxel-based morphometry study to explore the relationships between semantic and shape categorization tasks and brain morphometric differences in 50 controls. We found significant correlation between categorization performance and the volume of the grey matter in the right anterior middle and inferior temporal gyri. Semantic categorization tasks were associated with more rostral temporal regions than shape categorization tasks. A significant relationship was also shown between white matter volume in the right temporal lobe and performance in the semantic tasks. Tractography revealed that this white matter region involved several projection and association fibers, including the arcuate fasciculus, inferior fronto-occipital fasciculus, uncinate fasciculus, and inferior longitudinal fasciculus. These results suggest that categorization abilities are supported by the anterior portion of the right temporal lobe and its interaction with other areas.

Highlights

Anterior temporal lobe morphometry correlates with categorization performances

Semantic is associated with a more rostral temporal region than shape categorization

Semantic categorization performances are associated with right temporal connections
“A mosquito bites and a butterfly flies": a specific response type of frontal patients in a similarity task
Authors: Garcin Béatrice , Volle Emmanuelle , Funkiewiez Aurélie , Miller Bruce L , Dubois Bruno , Levy Richard
Published: November 2017

Background

Patients with neurodegenerative diseases affecting the frontal lobes have difficulties in categorization tasks, such as the similarity tasks. They give two types of unusual response to the question: “In what way are an orange and a banana alike?”, either a differentiation (“one is yellow, the other is orange”) or a concrete similarity (“they are sweet”).

Objective

To characterize the categorization deficit of frontal patients and develop a short diagnostic tool to assess the nature of these difficulties.

Method

We analyzed the responses provided by frontal and non-frontal neurodegenerative patients in a novel verbal similarity task (SimiCat). We included 40 frontal patients with behavioral variant fronto-temporal dementia (bvFTD) and progressive supranuclear palsy (PSP), 23 patients with Alzheimer’s disease (AD) and 41 healthy matched controls. Responses that did not correspond to the expected taxonomic category (e.g.: fruits) were considered as errors.

Results

All patients groups were impaired at the SimiCat test compared to controls. Differentiation errors were specific of frontal patients. Receiver operating characteristic analyses showed that a cut-off of two differentiation errors or more achieved 85% sensitivity of 100% specificity to discriminate bvFTD from AD. A short version of the test (<5 min) showed similar discriminative validity as the full version.

Conclusion

Differentiation responses were specific of frontal patients. The SimiCat demonstrates good discriminative validity to differentiate bvFTD and AD. The short version of the test is a promising diagnostic tool that will need validation in future studies.
PI(4,5)P2forms dynamic cortical structures and directs actin distribution and cell polarity in C. elegans embryos
Authors: Scholze Melina J. , Barbieux Kévin S. , De Simone Alessandro , Boumasmoud Mathilde , Süess Camille C. N. , Wang Ruijia , Gönczy Pierre
Published: November 2017

Asymmetric division is crucial for embryonic development and stem cell lineages. In the one-cellC. elegansembryo, a contractile cortical actomyosin network contributes to anterior-posterior (A-P) polarity and asymmetric division by segregating PAR proteins to discrete cortical domains. Here, we discovered that the plasma membrane lipid phosphatidylinositol 4,5-bisphosphate (PIP2) forms dynamic structures inC. eleganszygotes, distributing in a polarized and PAR-dependent manner along the A-P axis. PIP2cortical structures overlap with F-actin and coincide with the actin regulators RHO-1, CDC-42 and ECT-2. Particle image velocimetry analysis revealed that PIP2and F-actin cortical movements are coupled, with PIP2structures moving slightly ahead. Importantly, we established that PIP2cortical structures form in an actin-dependent manner and, conversely, that decreasing or increasing the level of PIP2results in severe F-actin disorganization, revealing the interdependence between these components. Furthermore, we uncovered that PIP2regulates the sizing of PAR cortical domains. Overall, our work establishes for the first time that a lipid membrane component, PIP2, is a critical modulator of actin organization and cell polarity inC. elegansembryos.

Summary statement

PI(4,5)P2is distributed in dynamic cortical structures and regulates asymmetric division by controlling actin organization and cell polarity in the one-cellC. elegansembryo.
White LED Lighting for Plants
Authors: Sharakshane Anton
Published: November 2017

The highest intensity of photosynthesis is obtained under red light, but plants die or their growth gets disrupted if only red light is used. For example, Korean researchers [1] have shown that under pure red light the amount of the grown lettuce is greater than under a combination of red and blue light, but the leaves have a significantly smaller amount of chlorophyll, polyphenols and antioxidants. And the researchers at the Faculty of Biology of the Moscow State University [2] have found that the synthesis of sugars is reduced, growth is inhibited and no blossoming occurs in the leaves of Chinese cabbage under narrow-band red and blue light (as compared to a sodium lamp).

What kind of lighting is needed to get a fully developed, large, fragrant and tasty plant with moderate energy consumption?
Automatic sorting system for large calcium imaging data
Authors: Takekawa Takashi , Asai Hirotaka , Ohkawa Noriaki , Nomoto Masanori , Okubo-Suzuki Reiko , Ghandour Khaled , Sato Masaaki , Hayashi Yasunori , Inokuchi Kaoru , Fukai Tomoki
Published: November 2017

It has become possible to observe neural activity in freely moving animals via calcium imaging using a microscope, which could not be observed previously. However, it remains difficult to extract the dynamics of nerve cells from the recorded imaging data. In this study, we greatly improved the stability, and robustness of the cell activity estimation method via non-negative matrix decomposition with shrinkage estimation of the baseline. In addition, by improving the initial state of the iterative algorithm using a newly proposed method to extract the shape of the cell via image processing, a solution could be obtained with a small number of iterations. These methods were applied to artificial and real data, and their effectiveness was confirmed.
Predicting Cancer Drug Response Using a Recommender System
Authors: Supahvilai Chayaporn , Bertrand Denis , Nagarajan Niranjan
Published: November 2017

Motivation

As we move towards an era of precision medicine, the ability to predict patient-specific drug responses in cancer based on molecular information such as gene expression data represents both an opportunity and a challenge. In particular, methods are needed that can accommodate the high-dimensionality of data to learn interpretable models capturing drug response mechanisms, as well as providing robust predictions across datasets.

Results

We propose a method based on ideas from “recommender systems” (CaDRReS) that predicts cancer drug responses for unseen cell-lines/patients based on learning projections for drugs and cell-lines into a latent “pharmacogenomic” space. Comparisons with other proposed approaches for this problem based on large public datasets (CCLE, GDSC) shows that CaDRReS provides consistently good models and robust predictions even across unseen patient-derived cell-line datasets. Analysis of the pharmacogenomic spaces inferred by CaDRReS also suggests that they can be used to understand drug mechanisms, identify cellular subtypes, and further characterize drug-pathway associations.

Availability

Source code and datasets are available athttps://github.com/CSB5/CaDRReS

Contact

nagarajann@gis.a-star.edu.sg

Supplementary information

Supplementary data are available online.
Inferring amino acid interactions underlying protein function
Authors: Salinas Victor H. , Ranganathan Rama
Published: November 2017

Protein function arises from a poorly defined pattern of cooperative energetic interactions between amino acid residues. Strategies for deducing this pattern have been proposed, but lack of benchmark data has limited experimental verification. Here, we extend deep-mutation technologies to enable measurement of many thousands of pairwise amino acid couplings in members of a protein family. The data show that despite great evolutionary divergence, homologous proteins conserve a sparse, spatially distributed network of cooperative interactions between amino acids that underlies function. This pattern is quantitatively captured in the coevolution of amino acid positions, especially as indicated by the statistical coupling analysis (SCA), providing experimental confirmation of the key tenets of this method. This work establishes a clear link between physical constraints on protein function and sequence analysis, enabling a general practical approach for understanding the structural basis for protein function.
Stoichiometry and compositional plasticity of the yeast nuclear pore complex revealed by quantitative fluorescence microscopy
Authors: Rajoo Sasikumar , Vallotton Pascal , Onischenko Evgeny , Weis Karsten
Published: November 2017

The nuclear pore complex (NPC) is an 8-fold symmetrical channel providing selective transport of biomolecules across the nuclear envelope. Each NPC consists of ~30 different nuclear pore proteins (Nups) all present in multiple copies per NPC. Significant progress has recently been made in the characterization of the vertebrate NPC structure, however, because of the estimated size differences between the vertebrate and yeast NPC, it has been unclear whether the NPC architecture is conserved between species. Here, we have developed a quantitative image analysis pipeline, termed Nuclear Rim Intensity Measurement or NuRIM, to precisely determine copy numbers for almost all Nups within native NPCs of budding yeast cells. Our analysis demonstrates that the majority of yeast Nups are present at most in 16 copies per NPC. This reveals a dramatic difference to the stoichiometry determined for the human NPC suggesting that despite a high degree of individual Nup conservation, the yeast and human NPC architecture is significantly different. Furthermore, using NuRIM we examined the effects of mutations on NPC stoichiometry. We demonstrate for two paralog pairs of key scaffold Nups, Nup170/Nup157 and Nup192/Nup188 that their altered expression leads to significant changes in Nup stoichiometry inducing either voids in the NPC structure or substitution of one paralog by the other. Thus, our results not only provide accurate stoichiometry information for the intact yeast NPC but also reveal an intriguing compositional plasticity of the NPC architecture, which may explain how differences in NPC composition could arise in the course of evolution.

Significance

The nuclear pore complex (NPC) is one of the largest protein complexes in eukaryotes comprising over 500 nucleoporin subunits. The NPC is essential for transport of biomolecules across the nuclear envelope, however, due to its enormous size, it has been a challenge to characterize its molecular architecture. Herein, we have developed a novel, widely applicable imaging pipeline to determine the absolute nucleoporin abundances in native yeast NPCs. This reveals that the NPC composition dramatically differs between yeast and human despite an overall conservation of individual subunits. We also applied our imaging pipeline to examine yeast mutants revealing a remarkable compositional plasticity of NPCs. Our stoichiometry analyses provide an important resource for the generation of high-resolution structure models of the NPC.
The Long and the Short of Serotonergic Stimulation: Optogenetic activation of dorsal raphe serotonergic neurons changes the learning rate for rewards
Authors: Iigaya Kiyohito , Fonseca Madalena S. , Murakami Masayoshi , Mainen Zachary F. , Dayan Peter
Published: November 2017

Serotonin plays an influential, but computationally obscure, modulatory role in many aspects of normal and dysfunctional learning and cognition. Here, we studied the impact of optogenetic stimulation of dorsal raphe serotonin neurons in mice performing a non-stationary, reward-driven, foraging task. We report that activation of serotonin neurons significantly boosted learning rates for choices following long inter-trial-intervals that were driven by the recent history of reinforcement.
The genome sequence of the wild tomatoSolanum pimpinellifoliumprovides insights into salinity tolerance
Authors: Razali Rozaimi , Bougouffa Salim , Morton Mitchell J. L. , Lightfoot Damien J. , Alam Intikhab , Essack Magbubah , Arold Stefan T. , Kamau Allan , Schmöckel Sandra M. , Pailles Yveline , Shahid Mohammed , Michell Craig T. , Al-Babili Salim , Ho Yung Shwen , Tester Mark , Bajic Vladimir B. , Negrão Sónia
Published: November 2017

Solanum pimpinellifolium, a wild relative of cultivated tomato, offers a wealth of breeding potential for several desirable traits such as tolerance to abiotic and biotic stresses. Here, we report the genome and annotation ofS. pimpinellifolium‘LA0480’. The ‘LA0480’ genome size (811 Mb) and the number of annotated genes (25,970) are within the range observed for other sequenced tomato species. We developed and utilized the Dragon Eukaryotic Analyses Platform (DEAP) to functionally annotate the ‘LA0480’ protein-coding genes. Additionally, we used DEAP to compare protein function betweenS. pimpinellifoliumand cultivated tomato. Our data suggest enrichment in genes involved in biotic and abiotic stress responses. Moreover, we present phenotypic data from one field experiment that demonstrate a greater salinity tolerance for fruit-and yield-related traits inS. pimpinellifoliumcompared with cultivated tomato. To understand the genomic basis for these differences inS. pimpinellifoliumandS. lycopersicum, we analyzed 15 genes that have previously been shown to mediate salinity tolerance in plants. We show thatS. pimpinellifoliumhas a higher copy number of the inositol-3-phosphate synthase and phosphatase genes, which are both key enzymes in the production of inositol and its derivatives. Moreover, our analysis indicates that changes occurring in the inositol phosphate pathway may contribute to the observed higher salinity tolerance in ‘LA0480’. Altogether, our work provides essential resources to understand and unlock the genetic and breeding potential ofS. pimpinellifolium, and to discover the genomic basis underlying its environmental robustness.
DHX36 binding at G-rich sites in mRNA untranslated regions promotes translation
Authors: Sauer Markus , Juranek Stefan , Kazemier Hinke G. , Benhalevy Daniel , Wang Xiantao , Hafner Markus , Paeschke Katrin
Published: November 2017

Translation efficiency can be affected by mRNA stability and secondary structures, including so-called G-quadruplex (G4) structures. The highly conserved and essential DEAH-box helicase DHX36/RHAU is able to resolve G4 structures on DNA and RNA in vitro, however a system-wide analysis of DHX36 targets and function is lacking. We globally mapped DHX36 occupancy in human cell lines and found that it preferentially binds to G-rich sequences in the coding sequences (CDS) and 5' and 3' untranslated regions (UTR) of more than 4,500 mRNAs. Functional analyses, including RNA sequencing, ribosome footprinting, and quantitative mass spectrometry revealed that DHX36 decreased target mRNA stability. However, target mRNA accumulation in DHX36 KO cells did not lead to a significant increase in ribosome footprints or protein output indicating that they were translationally incompetent. We hypothesize that DHX36 resolves G4 and other structures that interfere with efficient translation initiation.
Efficient CRISPR/Cas-mediated homologous recombination in the model diatomThalassiosira pseudonana
Authors: Belshaw Nigel , Grouneva Irina , Aram Lior , Gal Assaf , Hopes Amanda , Mock Thomas
Published: November 2017

CRISPR/Cas enables targeted genome editing in many different plant and algal species including the model diatomThalassiosira pseudonana. However, efficient gene targeting by homologous recombination (HR) to date is only reported for photosynthetic organisms in their haploid life-cycle phase and there are no examples of efficient nuclease-meditated HR in any photosynthetic organism. Here, a CRISPR/Cas construct, assembled using Golden Gate cloning, enabled highly efficient HR for the first time in a diploid photosynthetic organism. HR was induced inT. pseudonanaby means of sequence specific CRISPR/Cas, paired with a donor matrix, generating substitution of the silacidin gene by a resistance cassette (FCP:NAT). Approximately 85% of NAT resistantT. pseudonanacolonies screened positive for HR using a nested PCR approach and confirmed by sequencing of the PCR products. The knockout of the silacidin gene inT. pseudonanacaused a significant increase in cell size, confirming the role of this gene for cell-size regulation in centric diatoms. Highly efficient gene targeting by HR makesT. pseudonanaas genetically tractable asNannochloropsisandPhyscomitrella, hence rapidly advancing functional diatom biology, bionanotechnology and any biotechnological application targeted on harnessing the metabolic potential of diatoms.
A bacterial effector directly targets Arabidopsis Argonaute 1 to suppress Pattern-triggered immunity and cause disease
Authors: Thiébeauld Odon , Charvin Magali , Singla-Rastogi Meenu , Perez-Quintero Alvaro L , Yang Fan , Pontier Dominique , Barraud Pierre , Pouzet Cécile , Bapaume Laure , Amesefe Delase , Li Guangyong , Deslandes Laurent , Lagrange Thierry , Alfano James R. , Navarro Lionel
Published: November 2017

Pseudomonas syringaetype III effectors were previously shown to suppress the Arabidopsis microRNA (miRNA) pathway through unknown mechanisms. Here, we first show that the HopT1-1 effector promotes bacterial growth by suppressing the Arabidopsis Argonaute 1 (AGO1)-dependent miRNA pathway. We further demonstrate that HopT1-1 interacts with Arabidopsis AGO1 through conserved glycine/tryptophan (GW) motifs, and in turn suppresses miRNA function. This process is not associated with a general decrease in miRNA accumulation. Instead, HopT1-1 reduces the level of AGO1-associated miRNAs in a GW-dependent manner. Therefore, HopT1-1 alters AGO1-miRISC activity, rather than miRNA biogenesis or stability. In addition, we show that the AGO1-binding platform of HopT1-1 is essential to suppress the production of reactive oxygen species (ROS) and of callose deposits during Pattern-triggered immunity (PTI). These data imply that the RNA silencing suppression activity of HopT1-1 is intimately coupled with its virulence function. Overall, these findings provide sound evidence that a bacterial effector has evolved to directly target a plant AGO protein to suppress PTI and cause disease.
Centromeric DNA destabilizes H3 nucleosomes to promote CENP-A deposition during the cell cycle
Authors: Shukla Manu , Pin Tong , White Sharon A. , Singh Puneet P. , Reid Angus M. , Sandra Catania , Pidoux Alison L. , Allshire Robin C.
Published: November 2017

Active centromeres are defined by the presence of nucleosomes containing CENP-A, a histone H3 variant, which alone is sufficient to direct kinetochore assembly. Once assembled at a location CENP-A chromatin and kinetochores are maintained at that location though a positive feedback loop where kinetochore proteins recruited by CENP-A itself promote deposition of new CENP-A following replication. Although CENP-A chromatin itself is a heritable entity, it is normally associated with specific sequences. Intrinsic properties of centromeric DNA may favour the assembly of CENP-A rather than H3 nucleosomes. Here we investigate histone dynamics on centromeric DNA. We show that during S-phase histone H3 is deposited as a placeholder at fission yeast centromeres and is subsequently evicted in G2 when we detect deposition of the majority of new CENP-ACnp1. We also find that centromeric DNA has an innate property of driving high rates of turnover of H3 containing nucleosomes resulting in low nucleosome occupancy. When placed at an ectopic chromosomal location in the absence of any CENP-ACnp1assembly, centromeric DNA retains its ability to impose S-phase deposition and G2 eviction of H3, suggesting that features within this DNA program H3 dynamics. As RNAPII occupancy on this centromere DNA coincides with H3 eviction in G2, we propose a model in which RNAPII-coupled chromatin remodelling promotes replacement of H3 with CENP-ACnp1nucleosomes.
Mannan molecular sub-structures control nanoscale glucan exposure in Candida
Authors: Graus Matthew S. , Wester Michael J. , Lowman Douglas W. , Williams David L. , Kruppa Michael D. , Young Jesse M. , Pappas Harry C. , Lidke Keith A. , Neumann Aaron K.
Published: November 2017

N-linked mannans (N-mannans) in the cell wall of Candida albicans are thought to mask β-(1,3)-glucan from recognition by Dectin-1, contributing to innate immune evasion. Lateral cell wall exposures of glucan on Candida albicans are predominantly single receptor-ligand interaction sites and are restricted to nanoscale geometries. Candida species exhibit a range of basal glucan exposures and their mannans also vary in size and complexity at the molecular level. We used super resolution fluorescence imaging and a series of protein mannosylation mutants in C. albicans and C. glabrata to investigate the role of specific N-mannan features in regulating the nanoscale geometry of glucan exposure. Decreasing acid labile mannan abundance and α-(1,6)-mannan backbone length correlated most strongly with increased density and nanoscopic size of glucan exposures in C. albicans and C. glabrata, respectively. Additionally, a C. albicans clinical isolate with high glucan exposure produced similarly perturbed N-mannan structures and exhibited similar changes to nanoscopic glucan exposure geometry. We conclude that acid labile N-mannan controls glucan exposure geometry at the nanoscale. Furthermore, variations in glucan nanoexposure characteristics are clinically relevant and are likely to impact the nature of the pathogenic surface presented to innate immunocytes at dimensions relevant to receptor engagement, aggregation and signaling.
Prefrontal cortex regulates amygdala response to threat in trait anxiety
Authors: Ironside Maria. , Browning Michael. , Ansari Tahereh L. , Harvey Christopher J. , Sekyi-Djan Mama N. , Bishop Sonia J. , Harmer Catherine J. , O’Shea Jacinta
Published: November 2017

Background

Highly co-morbid mood and anxiety disorders are associated with aberrant fronto-limbic signalling during emotional processing. Animal models suggest that hypoactive prefrontal cortex weakens top-down control of limbic structures, causing heightened limbic and behavioural reactivity to negative information. Here we tested for this causal mechanism in human trait anxiety. We reasoned that if dorsolateral prefrontal cortex controls amygdala response to affective information, then stimulation of that brain region should reduce the hyperactive amygdala threat responsivity seen in trait anxiety.

Methods

Using a within-subjects design, sixteen high-trait anxious females received active and sham transcranial direct current stimulation (tDCS) of the dorsolateral prefrontal cortex, in counterbalanced order, with sessions timed to be at least one month apart. Each session was followed immediately by a functional magnetic resonance imaging (fMRI) scan during which participants performed an attentional task with threat-related distractors.

Results

As predicted, compared to sham stimulation, active prefrontal cortex stimulation reduced amygdala threat reactivity and simultaneously increased activity in cortical regions associated with attentional control and improved task accuracy.

Conclusions

These results demonstrate a causal role for impoverished frontal regulation of amygdaloid function in attentional capture by threat in trait anxiety. The finding that prefrontal stimulation reduces amygdala threat reactivity acutely indicates a neurocognitive mechanism that could contribute to tDCS treatment effects in affective disorders.
Accurate Reconstruction of Microbial Strains from Metagenomic Sequencing Using Representative Reference Genomes
Authors: Zhou Zhemin , Luhmann Nina , Alikhan Nabil-Fareed , Quince Christopher , Achtman Mark
Published: November 2017

Exploring the genetic diversity of microbes within the environment through metagenomic sequencing first requires classifying these reads into taxonomic groups. Current methods compare these sequencing data with existing biased and limited reference databases. Several recent evaluation studies demonstrate that current methods either lack sufficient sensitivity for species-level assignments or suffer from false positives, overestimating the number of species in the metagenome. Both are especially problematic for the identification of low-abundance microbial species, e. g. detecting pathogens in ancient metagenomic samples. We present a new method, SPARSE, which improves taxonomic assignments of metagenomic reads. SPARSE balances existing biased reference databases by grouping reference genomes into similarity-based hierarchical clusters, implemented as an efficient incremental data structure. SPARSE assigns reads to these clusters using a probabilistic model, which specifically penalizes non-specific mappings of reads from unknown sources and hence reduces false-positive assignments. Our evaluation on simulated datasets from two recent evaluation studies demonstrated the improved precision of SPARSE in comparison to other methods for species-level classification. In a third simulation, our method successfully differentiated multiple co-existing Escherichia coli strains from the same sample. In real archaeological datasets, SPARSE identified ancient pathogens with ≤ 0.02% abundance, consistent with published findings that required additional sequencing data. In these datasets, other methods either missed targeted pathogens or reported non-existent ones. SPARSE and all evaluation scripts are available at https://github.com/zheminzhou/SPARSE.
Building a schizophrenia genetic network: Transcription Factor 4 regulates genes involved in neuronal development and schizophrenia risk
Authors: Xia Hanzhang , Jahr Fay M. , Kim Nak-Kyeong , Xie Linying , Shabalin Andrey A. , Bryois Julien , Sweet Douglas H. , Kronfol Mohamad M. , Palasuberniam Preetha , McRae MaryPeace , Riley Brien P. , Sullivan Patrick F. , van den Oord Edwin J. , McClay Joseph L.
Published: November 2017

The transcription factor 4 (TCF4) locus is a robust association finding with schizophrenia (SZ), but little is known about the genes regulated by the encoded transcription factor. Therefore, we conducted chromatin immunoprecipitation sequencing (ChIP-seq) of TCF4 in neural-derived (SH-SY5Y) cells to identify genome-wide TCF4 binding sites, followed by data integration with SZ association findings. We identified 11,322 TCF4 binding sites overlapping in two ChIP-seq experiments. These sites are significantly enriched for the TCF4 Ebox binding motif (>85% having ≥1 Ebox) and implicate a gene set enriched for genes down-regulated in TCF4 siRNA knockdown experiments, indicating the validity of our findings. The TCF4 gene set was also enriched among 1) Gene Ontology categories such as axon/neuronal development, 2) genes preferentially expressed in brain, in particular pyramidal neurons of the somatosensory cortex, and 3) genes down-regulated in post-mortem brain tissue from SZ patients (OR=2.8, permutation p<4x10−5). Considering genomic alignments, TCF4 binding sites significantly overlapped those for neural DNA binding proteins such as FOXP2 and the SZ-associated EP300. TCF4 binding sites were modestly enriched among SZ risk loci from the Psychiatric Genomic Consortium (OR=1.56, p=0.03). In total, 130 TCF4 binding sites occurred in 39 of the 108 regions published in 2014. Thirteen genes within the 108 loci had both a TCF4 binding site ±10kb and were differentially expressed in siRNA knockdown experiments of TCF4, suggesting direct TCF4 regulation. These findings confirm TCF4 as an important regulator of neural genes and point towards functional interactions with potential relevance for SZ.
Electrical stimulation in hippocampus and entorhinal cortex impairs spatial and temporal memory
Authors: Goyal Abhinav , Miller Jonathan , Watrous Andrew J. , Lee Sang Ah , Coffey Tom , Sperling Michael R. , Sharan Ashwini , Worrell Gregory , Berry Brent , Lega Bradley , Jobst Barbara , Davis Kathryn A. , Inman Cory , Sheth Sameer A. , Wanda Paul A. , Ezzyat Youssef , Das Sandhitsu R. , Stein Joel , Gorniak Richard , Jacobs Joshua
Published: November 2017

The medial temporal lobe (MTL) is widely implicated in supporting episodic memory and navigation, but its precise functional role in organizing memory across time and space remains elusive. Here we examine the specific cognitive processes implemented by MTL structures (hippocampus and entorhinal cortex) to organize memory by using electrical brain stimulation, leveraging its ability to establish causal links between brain regions and features of behavior. We studied neurosurgical patients of both sexes who performed spatial-navigation and verbal-episodic memory tasks while brain stimulation was applied in various regions during learning. During the verbal memory task, stimulation in the MTL disrupted the temporal organization of encoded memories such that items learned with stimulation tended to be recalled in a more randomized order. During the spatial task, MTL stimulation impaired subjects’ abilities to remember items located far away from boundaries. These stimulation effects were specific to the MTL. Our findings thus provide the first causal demonstration in humans of the specific memory processes that are performed by the MTL to encode when and where events occurred.

Significance Statement

Numerous studies have implicated the medial temporal lobe (MTL) in encoding spatial and temporal memories, but they have not been able to causally demonstrate the nature of the cognitive processes by which this occurs in real-time. Electrical brain stimulation is able to demonstrate causal links between a brain region and a given function with high temporal precision. By examining behavior in a memory task as subjects received MTL stimulation, we provide the first causal evidence demonstrating the role of the MTL in organizing the spatial and temporal aspects of episodic memory.
Identifying the phenotypic effect of rare variants by including between-pedigree coancestry in variance components linkage analysis
Authors: Hicks J.E. , Province M. A.
Published: November 2017

The contribution of rare variants to disease burden has become an important focus in genetic epidemiology. These effects are difficult to detect in population-based datasets, and as a result, interest in family-based study designs has resurfaced. Linkage analysis tools will need to be updated to accommodate the scale of data generated by modern genotyping and sequencing technologies.

In conventional linkage analysis individuals in different pedigrees are assumed to be independent of each other. However, cryptic relatedness is often present in populations and haplotypes that harbor rare variants may be shared between pedigrees as well as within them.

With millions of polymorphisms, Identity-by-descent (IBD) states across the genome can now be inferred without use of pedigree information. This is done by identifying long runs of identical-by-state genotypes which are unlikely to arise without IBD. Previously, IBD had to be estimated in pedigrees from recombination events in a sparse set of markers.

We present a method for variance-components linkage that can incorporate large number of markers and allows for between-pedigree relatedness. We replace the IBD matrix generated from pedigree-based analysis with one generated from a genotype-based method. All pedigrees in a dataset are considered jointly, allowing between-pedigree IBD to be included in the model.

In simulated data, we show that power is increased in the scenario when there is a haplotype shared IBD between members of different pedigrees. If there is no between-pedigree IBD, the analysis reduces to conventional variance-components analysis. By determining IBD states by long runs of dense IBS genotypes, linkage signals can be determined from their physical position, allowing more precise localization.
Control of Genetic Parasites Mediated Through Nucleoporin Evolution
Authors: Rowley Paul A. , Patterson Kurt , Sandmeyer Suzanne B. , Sawyer Sara L.
Published: November 2017

Yeasts serve as long-term hosts to several types of genetic parasites. Few studies have addressed the evolutionary trajectory of yeast genes that control the stable co-existence of these parasites with their host cell. InSaccharomycesyeasts, the retrovirus-like Ty retrotransposons must access the nucleus. We show that several genes encoding components of the yeast nuclear pore complex have experienced natural selection for substitutions that change the encoded protein sequence. By replacing theseS. cerevisiaegenes with orthologs from otherSaccharomycesspecies, we discovered that natural sequence changes have affected the control of Ty retrotransposons. Specifically, changing the genetic sequence ofNUP84orNUP82to what is found in otherSaccharomycesspecies alters the retrotransposition ofS. cerevisiaeTy1 and Ty3, respectively. Importantly, all tested housekeeping functions ofNUP84andNUP82remained equivalent across species. The nuclear pore complex is the gatekeeper of the nucleus. It appears that nucleoporins are adapting to modulate the control of genetic parasites which access the nucleus, which is achieved despite the strict constraints imposed by host nuclear pore complex function.
Panaconda: Application of pan-synteny graph models to genome content analysis
Authors: Warren Andrew S. , Davis James J. , Wattam Alice R. , Machi Dustin , Setubal João C. , Heath Lenwood S.
Published: November 2017

Motivation

Whole-genome alignment and pan-genome analysis are useful tools in understanding the similarities and differences of many genomes in an evolutionary context. Here we introduce the concept of pan-synteny graphs, an analysis method that combines elements of both to represent conservation and change of multiple prokaryotic genomes at an architectural level. Pan-synteny graphs represent a reference free approach for the comparison of many genomes and allows for the identification of synteny, insertion, deletion, replacement, inversion, recombination, missed assembly joins, evolutionary hotspots, and reference based scaffolding.

Results

We present an algorithm for creating whole genome multiple sequence comparisons and a model for representing the similarities and differences among sequences as a graph of syntenic gene families. As part of the pan-synteny graph creation, we first create a de Bruijn graph. Instead of the alphabet of nucleotides commonly used in genome assembly, we use an alphabet of gene families. This de Bruijn graph is then processed to create the pan-synteny graph. Our approach is novel in that it explicitly controls how regions from the same sequence and genome are aligned and generates a graph in which all sequences are fully represented as paths. This method harnesses previous computation involved in protein family calculation to speed up the creation of whole genome alignment for many genomes. We provide the software suite Panaconda, for the calculation of pan-synteny graphs given annotation input, and an implementation of methods for their layout and visualization.

Availability

Panaconda is available athttps://github.com/aswarren/pangenome_graphsand datasets used in examples are available athttps://github.com/aswarren/pangenome_examples

Contact

Andrew Warrenanwarren@vt.edu
Preparation for mental effort recruits Dorsolateral Prefrontal Cortex: an fNIRS investigation
Authors: Vassena Eliana , Gerrits Robin , Demanet Jelle , Verguts Tom , Siugzdaite Roma
Published: November 2017

Preparing for a mentally demanding task calls upon cognitive and motivational resources. The underlying neural implementation of these mechanisms is receiving growing attention, given the implications for professional, social, and medical contexts. While several fMRI studies converge in assigning a crucial role to a cortico-subcortical network including Anterior Cigulate Cortex (ACC) and striatum, the involvement of Dorsolateral Prefrontal Cortex (DLPFC) during mental effort anticipation has yet to be replicated. This study was designed to target DLPFC contribution using functional Near Infrared Spectroscopy (fNIRS), as a more cost-effective tool measuring cortical hemodynamics. We adapted a validated mental effort task, where participants performed easy and difficult mental calculation, while measuring DLPFC activity during the anticipation phase. As hypothesized, DLPFC activity increased during preparation for a hard task as compared to an easy task. Besides replicating a previous fMRI study, these results establish fNIRS as an effective tool to investigate cortical contributions to preparation for effortful behavior. This is especially useful if one requires testing large samples (e.g., to target individual differences), populations with contraindication for functional MRI (e.g., infants or patients with metal implants), or subjects in more naturalistic environments (e.g., work or sport).
Formation and disassembly of a contractile actomyosin network mediates content release from large secretory vesicles
Authors: Segal Dagan , Zaritsky Assaf , Schejter Eyal D. , Shilo Ben-Zion
Published: November 2017

Secretion of adhesive glycoproteins to the lumen ofDrosophilalarval salivary glands is carried out by contraction of an actomyosin network that is assembled around large secretory vesicles, following their fusion to the apical membranes. We have identified a cycle of actin coat nucleation and disassembly that is independent of myosin. Recruitment of active Rho1 to the fused vesicle triggers activation of the formin Diaphanous and nucleation of linear actin. This, in turn, leads to actin-dependent localization of a RhoGAP protein that locally shuts off Rho1, promoting disassembly of the actin coat. Recruitment of the branched actin nucleation machinery is also required for effective Rho1 inactivation. Interestingly, different blocks to actin coat disassembly arrested vesicle contraction, indicating that actin turnover is an integral part of the actomyosin contraction cycle. The capacity of F-actin to trigger a negative feedback on its own production may be utilized in a variety of scenarios, to coordinate a succession of morphogenetic events or maintain homeostasis.

This work identified a cycle of actin assembly and disassembly in large secretory vesicles ofDrosophilasalivary glands. Actin disassembly is triggered by actin-dependent recruitment of a RhoGAP protein, and is essential for the contractility of the vesicle leading to content release to the lumen.
Aligning sequences to general graphs in O(V + mE) time
Authors: Rautiainen Mikko , Marschall Tobias
Published: November 2017

Graphs are commonly used to represent sets of sequences. Either edges or nodes can be labeled by sequences, so that each path in the graph spells a concatenated sequence. Examples include graphs to represent genome assemblies, such as string graphs and de Bruijn graphs, and graphs to represent a pan-genome and hence the genetic variation present in a population. Being able to align sequencing reads to such graphs is a key step for many analyses and its applications include genome assembly, read error correction, and variant calling with respect to a variation graph. Given the wide range of applications of this basic problem, it is surprising that algorithms with optimal runtime are, to the best of our knowledge, yet unknown. In particular, aligning sequences to cyclic graphs currently represents a challenge both in theory and practice. Here, we introduce an algorithm to compute the minimum edit distance of a sequence of length m to any path in a node-labeled directed graph (V, E) in O(|V |+m|E|) time and O(|V |) space. The corresponding alignment can be obtained in the same runtime using space. The time complexity depends only on the length of the sequence and the size of the graph. In particular, it does not depend on the cyclicity of the graph, or any other topological features.
Multiplexed temporally focused light shaping for high-resolution multi-cell targeting
Authors: Accanto Nicolò , Tanese Dimitrii , Ronzitti Emiliano , Molinier Clément , Newman Zachary L. , Wyart Claire , Isacoff Ehud , Papagiakoumou Eirini , Emiliani Valentina
Published: November 2017

Patterning light at the single-cell level over multiple neurons in the brain is crucial for optogenetic photostimulation that can recapitulate natural activity patterns and, thereby, determine the role of specific components of brain activity in behavior. To this end we have developed a method for projecting three-dimensional, 2-photon excitation patterns that are confined to many individual neurons. The new versatile optical scheme generates multiple extended excitation spots in a large volume with micrometric lateral and axial resolution. Two-dimensional temporally focused shapes are multiplexed several times over selected positions, thanks to the precise spatial phase modulation of the pulsed beam. This permits, under multiple configurations, the generation of tens of axially confined spots in an extended volume, spanning a range in depth of up to 500 μm. We demonstrate the potential of the approach by performing multi-cell volumetric excitation of photoactivatable GCaMP in the central nervous system of Drosophila larvae, a challenging structure with densely arrayed and small diameter neurons, and by photoconverting the fluorescent protein Kaede in zebrafish larvae. Our technique paves the way for the optogenetic manipulation of a large number of neurons in intact circuits.
Differential polarization of cortical pyramidal neuron dendrites through weak extracellular fields
Authors: Aspart Florian , Remme Michiel W.H. , Obermayer Klaus
Published: November 2017

The rise of transcranial current stimulation (tCS) techniques have sparked an increasing interest in the effects of weak extracellular electric fields on neural activity. These fields modulate ongoing neural activity through polarization of the neuronal membrane. While the somatic polarization has been investigated experimentally, the frequency-dependent polarization of the dendritic trees in the presence of alternating (AC) fields has received little attention yet. Using a biophysically detailed model with experimentally constrained active conductances, we analyze the subthreshold response of cortical pyramidal cells to weak AC fields, as induced during tCS. We observe a strong frequency resonance around 10-20 Hz in the apical dendrites sensitivity to polarize in response to electric fields but not in the basal dendrites nor the soma. To disentangle the relative roles of the cell morphology and active and passive membrane properties in this resonance, we perform a thorough analysis using simplified models, e.g. a passive pyramidal neuron model, simple passive cables and reconstructed cell model with simplified ion channels. We attribute the origin of the resonance in the apical dendrites to (i) a locally increased sensitivity due to the morphology and to (ii) the high density of h-type channels. Our systematic study provides an improved understanding of the subthreshold response of cortical cells to weak electric fields and, importantly, allows for an improved design of tCS stimuli.
The microbiome and resistome of hospital sewage during passage through the community sewer system
Authors: Buelow Elena , Bayjanov Jumamurat R. , Willems Rob J.L. , Bonten Marc J.M. , Schmitt Heike , van Schaik Willem
Published: November 2017

Effluents from wastewater treatment plants (WWTPs) have been proposed to act as point sources of antibiotic-resistant bacteria (ARB) and antimicrobial resistance genes (ARGs) in the environment. Hospital sewage may contribute to the spread of ARB and ARGs as it contains the feces and urine of hospitalized patients, who are more frequently colonized with multi-drug resistant bacteria than the general population. However, whether hospital sewage noticeably contributes to the quantity and diversity of ARGs in the general sewerage system has not yet been determined.

Here, we employed culture-independent techniques, namely 16S rRNA and nanolitre-scale quantitative PCRs, to describe the role of hospital effluent as a point source of ARGs in the sewer system, through comparing microbiota composition and levels of ARGs in hospital sewage with WWTP influent, WWTP effluent and the surface water in which the effluent is released.

Compared to other sample sites, hospital sewage was richest in human-associated bacteria and contained the highest relative levels of ARGs. Yet, the abundance of ARGs was comparable in WWTPs with and without hospital wastewater, suggesting that hospitals do not contribute to the spread of ARGs in countries with a functioning sewerage system.