bluuebunny/crossref_metadata_2025 huggingface dataset:
Age-Related Changes in the Neural Dynamics of Bottom-Up and Top-Down Processing During Visual Object Recognition: An Electrophysiological Investigation
Authors: Lai Leslie Y. , Frömer Romy , Festa Elena K. , Heindel William C.
Published: April 2019

When recognizing objects in our environments, we rely on both what we see and what we know. While elderly adults have been found to display increased sensitivity to top-down influences of contextual information during object recognition, the locus of this increased sensitivity remains unresolved. To address this issue, we examined the effects of aging on the neural dynamics of bottom-up and top-down visual processing during rapid object recognition. Specific EEG ERP components indexing bottom-up and top-down processes along the visual processing stream were assessed while systematically manipulating the degree of object ambiguity and scene context congruity. An increase in early attentional feedback mechanisms (as indexed by N1) as well as a functional reallocation of executive attentional resources (as indexed by P200) prior to object identification were observed in elderly adults, while post-perceptual semantic integration (as indexed by N400) remained intact. These findings suggest that compromised bottom-up perceptual processing of visual input in healthy aging leads to an increased involvement of top-down processes to resolve greater perceptual ambiguity during object recognition.
A Pandas complex adapted for piRNA-guided transposon silencing
Authors: Zhao Kang , Cheng Sha , Miao Na , Xu Ping , Lu Xiaohua , Zhang Yuhan , Wang Ming , Ouyang Xuan , Yuan Xun , Liu Weiwei , Lu Xin , Zhou Peng , Gu Jiaqi , Zhang Yiqun , Qiu Ding , Jin Zhaohui , Su Chen , Peng Chao , Wang Jian-Hua , Dong Meng-Qiu , Wan Youzhong , Ma Jinbiao , Cheng Hong , Huang Ying , Yu Yang
Published: April 2019

The repression of transposons by the Piwi-interacting RNA (piRNA) pathway is essential to protect animal germ cells. In Drosophila ovaries, Panoramix (Panx) enforces transcriptional silencing by binding to the target-engaged Piwi-piRNA complex, although the precise mechanisms by which this occurs remain elusive. Here, we show that Panx functions together with a germline specific paralogue of a nuclear export factor, dNxf2, and its cofactor dNxt1 (p15), as a ternary complex to suppress transposon expression. Structural and functional analyses demonstrate that dNxf2 binds Panx via its UBA domain, which plays an important role in transposon silencing. Unexpectedly, dNxf2 interacts directly with dNxf1 (TAP), a general nuclear export factor. As a result, dNxf2 prevents dNxf1 from binding to the FG repeats of the nuclear pore complex, a process required for proper RNA export. Transient tethering of dNxf2 to nascent transcripts leads to their nuclear retention. Therefore, we propose that dNxf2 may function as a Pandas (Panoramix-dNxf2 dependent TAP/p15 silencing) complex, which counteracts the canonical RNA exporting machinery and restricts transposons to the nuclear peripheries. Our findings may have broader implications for understanding how RNA metabolism modulates epigenetic gene silencing and heterochromatin formation.
Resting-state directed brain connectivity patterns in adolescents from source-reconstructed EEG signals based on information flow rate
Authors: Hristopulos Dionissios , Babul Arif , Babul Shazia , Brucar Leyla R , Virji-Babul Naznin
Published: April 2019

Quantifying the brain's effective connectivity offers a unique window onto the causal architecture coupling the different regions of the brain. Here, we advocate a new, data-driven measure of directed (or effective) brain connectivity based on the recently developed information flow rate coefficient. The concept of the information flow rate is founded in the theory of stochastic dynamical systems and its derivation is based on first principles; unlike various commonly used linear and nonlinear correlations and empirical directional coefficients, the information flow rate can measure causal relations between time series with minimal assumptions. We apply the information flow rate to electroencephalography (EEG) signals in adolescent males to map out the directed, causal, spatial interactions between brain regions during resting-state conditions. To our knowledge, this is the first study of effective connectivity in the adolescent brain. Our analysis reveals that adolescents show a pattern of information flow that is strongly left lateralized, and consists of short and medium ranged bidirectional interactions across the frontal-central-temporal regions. These results suggest an intermediate state of brain maturation in adolescence.
Partial FMRP expression is sufficient to normalize neuronal hyperactivity in Fragile X neurons
Authors: Graef John D. , Wu Hao , Ng Carrie , Sun Chicheng , Villegas Vivian , Qadir Deena , Jesseman Kimberly , Warren Stephen T. , Jaenisch Rudolf , Cacace Angela , Wallace Owen
Published: April 2019

Fragile X Syndrome (FXS) is the most common genetic form of intellectual disability caused by a CGG repeat expansion in the 5’-UTR of the Fragile X mental retardation gene FMR1, triggering epigenetic silencing and the subsequent absence of the protein, FMRP. Reactivation of FMR1 represents an attractive therapeutic strategy targeting the genetic root cause of FXS. However, largely missing in the FXS field is an understanding of how much FMR1 reactivation is required to rescue FMRP-dependent mutant phenotypes. Here, we utilize FXS patient derived excitatory neurons to model FXS in vitro and confirm that the absence of FMRP leads to neuronal hyperactivity. We further determined the levels of FMRP and the percentage of FMRP positive cells necessary to correct this phenotype utilizing a mixed and mosaic neuronal culture system and a combination of CRISPR, antisense and expression technologies to titrate FMRP in FXS and WT neurons. Our data demonstrate that restoration of greater than 5% of overall FMRP expression levels or greater than 20% FMRP expressing neurons in a mosaic pattern is sufficient to normalize a FMRP-dependent, hyperactive phenotype in FXS iPSC-derived neurons.

Highlights

CRISPR gene editing to generate FMRP KO and CGG-deleted isogenic iPSCs

MEA as an approach to identify FMR1 dependent phenotype in NGN2 neurons derived from FXS and FMRP KO iPSCs

Cell mixing paradigm as mosaicism in a dish to rescue phenotype

Minimal level of FMRP determined by FMR1 mRNA and targeted demethylation of CGG repeats to correct the hyperactive phenotype in FXS neurons

ASO titration-validated partial expression of FMRP is sufficient to normalize increased neuronal activity
Reducing false positives in tractography with microstructural and anatomical priors
Authors: Schiavi Simona , Barakovic Muhamed , Ocampo-Pineda Mario , Descoteaux Maxime , Thiran Jean-Philippe , Daducci Alessandro
Published: April 2019

Tractography is a family of algorithms that use diffusion-weighted magnetic resonance imaging data to reconstruct the white matter pathways of the brain. Although it has been proven to be particularly effective for studying non-invasively the neuronal architecture of the brain, recent studies have highlighted that the large incidence of false positive connections retrieved by these techniques can significantly bias any connectivity analysis. Some solutions have been proposed to overcome this issue and the ones relying on convex optimization framework showed a significant improvement. Here we propose an evolution of the Convex Optimization Modeling for Microstructure Informed Tractography (COMMIT) framework, that combines basic prior knowledge about brain anatomy with group-sparsity regularization into the optimization problem. We show that the new formulation dramatically reduces the incidence of false positives in synthetic DW-MRI data.
VariCarta: a comprehensive database of harmonized genomic variants found in ASD sequencing studies
Authors: Belmadani Manuel , Jacobson Matthew , Holmes Nathan , Phan Minh , Pavlidis Paul , Rogic Sanja
Published: April 2019

Background

Recent years has seen a boom in the application of the next-generation sequencing technology to the study of human diseases, including Autism Spectrum Disorder (ASD), where the focus has been on identifying rare, possibly causative genomic variants in ASD individuals. Because of the high genetic heterogeneity of ASD, a large number of subjects is needed to establish evidence for a variant or gene ASD-association, thus aggregating data across cohorts and studies is necessary. However, methodological inconsistencies and subject overlap across studies complicate data aggregation.

Description

Here we present VariCarta, a web-based database developed to address these challenges by collecting, reconciling and consistently cataloguing literature-derived genomic variants found in ASD subjects using ongoing semi-manual curation. The careful manual curation combined with a robust data import pipeline rectifies errors, converts variants into a standardized format, identifies and harmonizes cohort overlaps and documents data provenance. The harmonization aspect is especially important since it prevents the potential double-counting of variants which can lead to inflation of gene-based evidence for ASD-association.

Conclusion

VariCarta is the largest collection of systematically curated, harmonized and comprehensively annotated literature-derived ASD-associated variants. The database currently contains 35,615 variant events from 8,044 subjects, collected across 50 publications, and reconciles 6,057 variants that have been reported in literature multiple times. VariCarta is freely accessible at http://varicarta.msl.ubc.ca.
Designer DNA architecture offers precise and multivalent spatial pattern-recognition for viral sensing and inhibition
Authors: Kwon Paul S. , Ren Shaokang , Kwon Seok-Joon , Kizer Megan E. , Kuo Lili , Zhou Feng , Zhang Fuming , Kim Domyoung , Fraser Keith , Kramer Laura D. , Seeman Nadrian C. , Dordick Jonathan S. , Linhardt Robert J. , Chao Jie , Wang Xing
Published: April 2019

DNA, when folded into nanostructures of customizable shapes, is capable of spacing and arranging external ligands in a desired geometric pattern with nanometer-precision. This allows DNA to serve as an excellent, biocompatible scaffold for complex spatial pattern-recognizing displays. In this report, we demonstrate that a templated designer DNA nanostructure achieves multi-ligand display with precise spatial pattern-recognition, representing a unique strategy in synthesizing potent viral sensors and inhibitors. Specifically, a star-shaped DNA architecture, carrying five molecular beacon-like motifs, was constructed to display ten dengue virus envelope protein domain-III (ED3)-binding aptamers into a 2D pattern precisely matching the pentagonal arrangement of ED3 clusters on the dengue viral surface. The resulting spatial pattern recognition and multivalent interactions achieve high dengue-binding avidity, conferring direct, highly-sensitive, facile, low-cost, and rapid sensing as well as potent viral inhibition capability. Our molecular-platform design strategy could be adapted to detect and combat other disease-causing pathogens, including bacteria and microbial-toxins, by generating the requisite ligand patterns on customized DNA nanoarchitectures.
Genomic selection for lentil breeding: empirical evidence
Authors: Haile Teketel A. , Heidecker Taryn , Wright Derek , Neupane Sandesh , Ramsay Larissa , Vandenberg Albert , Bett Kirstin E.
Published: April 2019

Genomic selection (GS) is a type of marker-based selection which was initially suggested for livestock breeding and is being encouraged for crop breeding. Several statistical models and approaches have been developed to implement GS; however, none of these methods have been tested for use in lentil breeding. This study was conducted to evaluate different GS models and prediction scenarios based on empirical data and to make recommendations for designing genomic selection strategies for lentil breeding. We evaluated nine single-trait models, two multiple-trait models, and models that account for population structure and genotype-by-environment interaction (GEI) using a lentil diversity panel and two recombinant inbred lines (RIL) populations that were genotyped using a custom exome capture assay. Within-population, across-population and across-environment predictions were made for five phenology traits. Prediction accuracy varied among the evaluated models, populations, prediction scenarios, traits, and statistical models. Single-trait models showed similar accuracy for each trait in the absence of large effect QTL but BayesB outperformed all models when there were QTL with relatively large effects. Models that accounted for GEI and multiple-trait (MT) models increased prediction accuracy for a low heritability trait by up to 66% and 14% but accuracy did not improve for traits of high heritability. Moderate to high accuracies were obtained for within-population and across-environment predictions but across-population prediction accuracy was very low. This suggests that GS can be implemented in lentil to make predictions within populations and across environments, but across-population prediction should not be considered when the population size is small.
CAncer bioMarker Prediction Pipeline (CAMPP) - A standardised and user-friendly framework for the analysis of quantitative biological data
Authors: Terkelsen Thilde , Krogh Anders , Papaleo Elena
Published: April 2019

Motivation

Recent improvements in -omics and next-generation sequencing (NGS) technologies, and the lowered costs associated with generating these types of data, have made the analysis of high-throughput datasets standard, both for forming and testing biomedical hypotheses. Alongside new wet-lab methodologies, our knowledge of how to normalise bio-data has grown extensively. By removing latent undesirable variances, we obtain standardised datasets, which can be more easily compared between studies. These advancements mean that non-experts in bioinformatics are now faced with the challenge of performing computational data analysis, pre-processing and visualisation. One example could be the analysis of biological data to pinpoint disease-related biomarkers for experimental validation. In this case, bio-researchers will desire an easy and standardised way of analysing high-throughput datasets.

Results

Here we present the CAncer bioMarker Prediction Pipeline (CAMPP), an open-source R-based wrapper intended to aid non-experts in bioinformatics with data analyses. CAMPP is called from a terminal command line and is supported by a user-friendly manual. The pipeline may be run on a local computer and requires little or no knowledge of programming. CAMPP performs missing value imputation and normalisation followed by (I) k-means clustering, (II) differential expression/abundance analysis, (III) elastic-net regression, (IV) correlation and co-expression network analyses, (V) survival analysis and (IV) protein-protein/miRNA-gene interaction networks. The pipeline returns tabular files and graphical representations of the results. We hope that CAMPP will assist biomedical researchers in the analysis of quantitative biological data, whilst ensuring an appropriate biostatistical framework.

Availability and Implementation

CAMPP is available athttps://github.com/ELELAB/CAMPP
Efficient enzyme coupling algorithms identify functional pathways in genome-scale metabolic models
Authors: Pradhan Dikshant , Papin Jason A. , Jensen Paul A.
Published: April 2019

Flux coupling identifies sets of reactions whose fluxes are “coupled" or correlated in genome-scale models. By identified sets of coupled reactions, modelers can 1.) reduce the dimensionality of genome-scale models, 2.) identify reactions that must be modulated together during metabolic engineering, and 3.) identify sets of important enzymes using high-throughput data. We present three computational tools to improve the efficiency, applicability, and biological interpretability of flux coupling analysis.

The first algorithm (cachedFCF) uses information from intermediate solutions to decrease the runtime of standard flux coupling methods by 10-100 fold. Importantly, cachedFCF makes no assumptions regarding the structure of the underlying model, allowing efficient flux coupling analysis of models with non-convex constraints.

We next developed a mathematical framework (FALCON) that incorporates enzyme activity as continuous variables in genome-scale models. Using data from gene expression and fitness assays, we verified that enzyme sets calculated directly from FALCON models are more functionally coherent than sets of enzymes collected from coupled reaction sets.

Finally, we present a method (delete-and-couple) for expanding enzyme sets to allow redundancies and branches in the associated metabolic pathways. The expanded enzyme sets align with known biological pathways and retain functional coherence. The expanded enzyme sets allow pathway-level analyses of genome-scale metabolic models.

Together, our algorithms extend flux coupling techniques to enzymatic networks and models with transcriptional regulation and other non-convex constraints. By expanding the efficiency and flexibility of flux coupling, we believe this popular technique will find new applications in metabolic engineering, microbial pathogenesis, and other fields that leverage network modeling.
Imaging Membrane Curvature inside a Model Immunological Synapse in RBL-2H3 Cells using TIRF Microscopy with Polarized Excitation
Authors: Machado Rosa , Bendesky Justin , Brown Madison , Spendier Kathrin , Hagen Guy M.
Published: April 2019

Total internal reflection fluorescence microscopy with polarized excitation (P-TIRF) can be used to image nanoscale curvature phenomena in live cells. We used P-TIRF to visualize rat basophilic leukemia cells (RBL-2H3 cells) coming into contact with a supported lipid bilayer, modeling an immunological synapse. These studies help correlate the dynamics of cell surface molecules with the mechanical properties of the plasma membrane during synapse formation.
A shared core microbiome in soda lakes separated by large distances
Authors: Zorz Jackie K. , Sharp Christine , Kleiner Manuel , Gordon Paul M.K. , Pon Richard T. , Dong Xiaoli , Strous Marc
Published: April 2019

In alkaline soda lakes, high concentrations of dissolved carbonates establish an environment favouring productive phototrophic microbial mat communities. Here we show how different species of microbial phototrophs and autotrophs contribute to this exceptional productivity. Four years of amplicon and shotgun DNA sequencing data from microbial mats from four different lakes indicated the presence of over 2,000 different species of Bacteria and Eukaryotes. Metagenome-assembled-genomes were obtained for a core microbiome of <100 abundant bacteria, which was shared among lakes and accounted for half of the extracted DNA throughout the four year sampling period. Most of the associated species were related to similar microbes previously detected in sediments of Central Asian alkaline soda lakes, showing that common selection principles drive community assembly from a globally distributed reservoir of alkaliphile biodiversity. Dispersal events between the two distant lake systems were shown to be extremely rare, with dispersal rates a function of abundance in microbial mats, but not sediments. Detection of more than 7,000 expressed proteins showed how phototrophic populations allocated resources to specific processes and occupied complementary niches. Carbon fixation only proceeded by the Calvin-Benson-Bassham cycle, detected in Cyanobacteria, Alphaproteobacteria, and, suprisingly, Gemmatomonadetes. Our study not only provides new fundamental insight into soda lake ecology, but also provides a template, guiding future efforts to engineer robust and productive biotechnology for carbon dioxide conversion.

Importance

Alkaline soda lakes are among the most productive ecosystems worldwide, despite their high pH. This high productivity leads to growth of thick “mats” of filamentous cyanobacteria. Here, we show that such mats have very high biodiversity, but at the same time contain a core, shared set of only approximately 100 different bacteria that perform key functions, such as photosynthesis. This “core microbiome” occurs both in Canadian and Central Asian soda lakes, >8,000 km apart. We present evidence for (very rare) dispersion of some core microbiome members from Canadian mats to Central Asian soda lake sediments. The close similarity between distant microbial communities indicates that these communities share common design principles, that reproducibly lead to a high and robust productivity. We unravel a few examples of such principles and speculate that these might be applied to create robust biotechnology for carbon dioxide conversion, to mitigate of global climate change.
Lytic transglycosylases RlpA and MltC assist inVibrio choleraedaughter cell separation
Authors: Weaver Anna I. , Jiménez-Ruiz Valeria , Tallavajhalla Srikar R. , Ransegnola Brett P. , Wong Kimberly Q. , Dörr Tobias
Published: April 2019

The cell wall is a crucial structural feature in the vast majority of bacteria and comprises a rigid, covalently closed, mesh-like network of peptidoglycan (PG) strands. While PG synthesis is important for bacterial survival under many conditions, the cell wall is also a dynamic structure, undergoing degradation and remodeling by so-called “autolysins”, enzymes that break bonds in the PG network. Cell division, for example, requires extensive PG remodeling and separation of daughter cells, which depends primarily upon the activity of amidases. However, inV. cholerae, we have found that amidase activity alone is insufficient for daughter cell separation and that the lytic transglycosylases RlpA and MltC both contribute to this process. MltC and RlpA both localize to the septum and are functionally redundant under normal laboratory conditions; however, only RlpA can support normal cell separation in low salt media. The division-specific activity of lytic transglycosylases has implications for the local structure of septal PG, suggesting that there may be glycan bridges between daughter cells that cannot be resolved by amidases. We propose that lytic transglycosylases at the septum serve as a back-up mechanism to cleave rare, stochastically produced PG strands that are crosslinked beyond the reach of the highly spatio-temporally limited activity of the amidase and to clear PG debris that may block the completion of outer-membrane invagination.
Experienced meditators exhibit no differences to demographically-matched controls in theta phase synchronisation, P200, or P300 during an auditory oddball task
Authors: Payne JR , Baell O , Geddes H , Fitzgibbon B , Emonson M , Hill AT , Van Dam NT , Humble G , Fitzgerald PB , Bailey NW
Published: April 2019

Objectives

Long-term meditation practice affects the brain’s ability to sustain attention. However, how this occurs is not well understood. Electroencephalography (EEG) studies have found that during dichotic oddball listening tasks, experienced meditators displayed altered attention-related neural markers including theta phase synchronisation (TPS) and event-related potentials (ERP; P200 and P300) to target tones while meditating compared to resting, and compared to non-meditators after intensive meditation interventions. Research is yet to establish whether the changes in the aforementioned neural markers are trait changes which may be observable in meditators irrespective of practice setting.

Method

The present study expanded on previous research by comparing EEG measures from a dichotic oddball task in a sample of community-based mindfulness meditators (n=22) to healthy controls with no meditation experience (n=22). To minimise state effects, neither group practiced meditation during / immediately prior to the EEG session.

Results

No group differences were observed in behavioural performance or either the global amplitude or distribution of theta phase synchronisation, P200 or P300. Bayes Factor analysis suggested evidence against group differences for the P200 and P300.

Conclusions

The results suggest that increased P200, P300 and TPS do not reflect trait-related changes in a community sample of mindfulness meditators. The present study used a larger sample size than previous research and power analayses suggested the study was suficiently powered to detect differences. These results add nuance to our understanding of which processes are affected by meditation and the amount of meditation required to generate differences in specific neural processes.
Extensive CD8β depletion does not prevent control of viral replication or protection from challenge in macaques chronically infected with a live attenuated simian immunodeficiency virus
Authors: Sutton Matthew S. , Ellis-Connell Amy , Balgeman Alexis J. , Barry Gabrielle , Weiler Andrea M. , Hetzel Scott J. , Zhou Yan , Kilby Annie , Mason Rosemarie D. , Biris Kristin K. , Mascola John R. , Sullivan Nancy J. , Roederer Mario , Friedrich Thomas C. , O’Connor Shelby L.
Published: April 2019

We evaluated the contribution of CD8αβ+ T cells on control of live-attenuated simian immunodeficiency virus (LASIV) replication during chronic infection and subsequent protection from pathogenic SIV challenge. Unlike previous reports with a CD8α-specific depleting monoclonal antibody (mAb), the CD8β-specific mAb CD8β255R1 selectively depleted CD8αβ+ T cells without also depleting non-CD8+ T cell populations that express CD8α, such as natural killer (NK) cells and γδ T cells. Following infusion with CD8β255R1, plasma viremia transiently increased coincident with declining peripheral CD8αβ+ T cells. Interestingly, plasma viremia returned to pre-depletion levels even when peripheral CD8αβ+ T cells did not. Although depletion of CD8αβ+ T cells in the lymph node (LN) was incomplete, frequencies of these cells were three-fold lower (p=0.006) in animals that received CD8β255R1 compared to control IgG. It is possible that these residual SIV-specific CD8αβ+ T cells may have contributed to suppression of viremia during chronic infection. We also determined whether infusion of CD8β255R1 in the LASIV-vaccinated animals increased their susceptibility to infection following intravenous challenge with pathogenic SIVmac239. We found that 7/8 animals infused with CD8β255R1, and 3/4 animals infused with the control IgG, were resistant to SIVmac239 infection. These results suggest that infusion with CD8β255R1 did not eliminate the protection afforded to LASIV vaccination. This provides a comprehensive description of the impact of CD8β255R1 infusion on the immunological composition of the host, when compared to an isotype matched control IgG, while showing that the control of LASIV viremia and protection from challenge can occur even after CD8β255R1 administration.

Importance

Studies of SIV-infected macaques that deplete CD8+ T cellsin vivowith monoclonal antibodies have provided compelling evidence for their direct antiviral role. These studies utilized CD8α-specific mAbs that target both the major (CD8αβ+) and minor (CD8αα+) populations of CD8+ T cells, but additionally deplete non-CD8+ T cell populations that express CD8α, such as NK cells and γδ T cells. In the current study, we administered the CD8β-specific depleting mAb CD8β255R1 to cynomolgus macaques chronically infected with a LASIV to selectively deplete CD8αβ+ T cells without removing CD8αα+ lymphocytes. We evaluated the impact on control of virus replication and protection from pathogenic SIVmac239 challenge. These results underscore the utility of CD8β255R1 for studying the direct contribution of CD8αβ+ T cells in various disease states.
miR-9 mediated noise optimization of the her6 oscillator is needed for cell state progression in the Zebrafish hindbrain
Authors: Soto Ximena , Biga Veronica , Kursawe Jochen , Lea Robert , Doostdar Parnian , Papalopulu Nancy
Published: April 2019

Ultradian oscillations of key transcription factors, such as members of the Hes family, are thought to be important in Neural Progenitor Cell (NPC) maintenance and miR-9 acts as a tuner of these oscillations in vitro. However, the existence and the role of such dynamic oscillatory expression in vivo is poorly understood. Here, we have generated a Zebrafish CRISPR knock-in Her6::venus fusion (Hes1 orthologue) to study endogenous dynamic gene expression in the embryonic hindbrain. We show that Her6 undergoes a transition from irregular, noisy, fluctuations to periodic oscillations as neurogenesis proceeds. In the absence of miR-9 input, noise in the Her6 oscillator increases and NPCs are unable to transit away from an intermediary state where they co-express progenitor and early differentiation markers. Thus, Her6 oscillations are facilitated by noise optimization mediated by miR-9 and this noise-tuning step is functionally important for cells to transition to differentiation.
Functional Territories of Human Dentate Nucleus
Authors: Guell Xavier , D’Mello Anila M , Hubbard Nicholas A , Romeo Rachel R , Gabrieli John DE , Whitfield-Gabrieli Susan , Schmahmann Jeremy D , Anteraper Sheeba Arnold
Published: April 2019

Anatomical connections link the cerebellar cortex with multiple distinct sensory, motor, association, and paralimbic areas of the cerebrum. These projections allow a topographically precise cerebellar modulation of multiple domains of neurological function, and underscore the relevance of the cerebellum for the pathophysiology of numerous disorders in neurology and psychiatry. The majority of fibers that exit the cerebellar cortex synapse in the dentate nuclei (DN) before reaching extracerebellar structures such as cerebral cortex. Although the DN have a central position in the anatomy of the cerebello-cerebral circuits, the functional neuroanatomy of human DN remains largely unmapped. Neuroimaging research has redefined broad categories of functional division in the human brain showing that primary processing, attentional (task positive) processing, and default-mode (task negative) processing are three central poles of neural macro-scale functional organization. This new macro-scale understanding of the range and poles of brain function has revealed that a broad spectrum of human neural processing categories (primary, task positive, task negative) is represented not only in the cerebral cortex, but also in the thalamus, striatum, and cerebellar cortex. Whether functional organization in DN obeys a similar set of macroscale divisions, and whether DN are yet another compartment of representation of a broad spectrum of human neural processing categories, remains unknown. Here we show for the first time that human DN is optimally divided into three functional territories as indexed by high spatio-temporal resolution resting-state MRI in 60 healthy adolescents, and that these three distinct territories contribute uniquely to default-mode, salience-motor, and visual brain networks. These conclusions are supported by novel analytical strategies in human studies of DN organization, including 64-channel MRI imaging, data-driven methods, and replication in an independent sample. Our findings provide a systems neuroscience substrate for cerebellar output to influence multiple broad categories of neural control - namely default- mode, attentional, and multiple unimodal streams of information processing including motor and visual. They also provide a validated data-driven mapping of functions in human DN, crucial for the design of methodology and interpretation of results in future neuroimaging studies of brain function and dysfunction.
Production and use of triploid zebrafish for surrogate reproduction
Authors: Franěk Roman , Tichopád Tomáš , Fučíková Michaela , Steinbach Christoph , Pšenička Martin
Published: April 2019

We report for first time comparison of two approaches for zebrafish triploid production using cold shock and heat shock treatment. Subsequently, produced triploid zebrafish were used as a recipients for intraperitoneal transplantation of ovarian and testicular cells originating from vas:EGFP strain in order to verify their suitability for surrogate reproduction. Heat shock treatment was far more effective evaluated as success rate of triploid production and viability in comparison to cold shock. Triploids were produced with up to 100% efficiency in particular females. As expected, all triploids were males. Subsequently, germ cells transplantation revealed that triploids are suitable surrogate hosts. Production of donor-derived sperm was achieved in 23% and 16% of triploids transplanted by testicular and ovarian cells, respectively. Success of the transplantation was confirmed by positive GFP signal detected in gonads of dissected fish and stripped sperm. Germline transmission was confirmed by fertilization tests followed by PCR analysis of embryos. Reproductive success of germline chimera triploids evaluated as fertilization rate and progeny development was comparable to control groups.
Whole-genome fingerprint of the DNA methylome during chemically induced differentiation of the human AML cell line HL-60/S4
Authors: Antwi Enoch Boasiako , Olins Ada , Teif Vladimir B , Bieg Matthias , Bauer Tobias , Gu Zuguang , Brors Benedikt , Eils Roland , Olins Donald , Ishaque Naveed
Published: April 2019

Background

Myeloid differentiation gives rise to a plethora of immune cells in the human body. This differentiation leaves strong signatures in the epigenome through each differentiated state of genetically identical cells. The leukemic HL-60/S4 promyelocytic cell can be easily differentiated from its undifferentiated promyelocyte state into neutrophil-and macrophage-like cell states, making it an excellent system for studying myeloid differentiation. In this study, we present the underlying genome and epigenome architecture of HL-60/S4 through its undifferentiated and differentiated cell states.

Results

We performed whole genome bisulphite sequencing of HL-60/S4 cells and their differentiated counterparts. With the support of karyotyping, we show that HL-60/S4 maintains a stable genome throughout differentiation. Analysis of differential CpG methylation reveals that most methylation changes occur in the macrophage-like state. Differential methylation of promoters was associated with immune related terms. Key immune genes, CEBPA, GFI1, MAFB and GATA1 showed differential expression and methylation. However, we observed strongest enrichment of methylation changes in enhancers and CTCF binding sites, implying that methylation plays a major role in large scale transcriptional reprogramming and chromatin reorganisation during differentiation. Correlation of differential expression and distal methylation with support from chromatin capture experiments allowed us to identify putative proximal and long-range enhancers for a number of immune cell differentiation genes, including CEBPA and CCNF. Integrating expression data, we present a model of HL-60/S4 differentiation in relation to the wider scope of myeloid differentiation.

Conclusions

For the first time, we elucidate the genome and CpG methylation landscape of HL-60/S4 during differentiation. We identify all differentially methylated regions and positions. We link these to immune function and to important factors in myeloid differentiation. We demonstrate that methylation plays a more significant role in modulating transcription via enhancer reprogramming, rather than by promoter regulation. We identify novel regulatory regions of key components in myeloid differentiation that are regulated by differential methylation. This study contributes another layer of “omics” characterisation of the HL-60/S4 cell line, making it an excellent model system for studying rapid in vitro cell differentiation.

Summary statement

Epigenomics plays a major role in cell identity and differentiation. We present the DNA methylation landscape of leukemic cells during in-vitro differentiation, to add another ‘omics layer to better understand the mechanisms behind differentiation.
Amygdala controls saccade and gaze physically, motivationally, and socially
Authors: Maeda Kazutaka , Inoue Ken-ichi , Kunimatsu Jun , Takada Masahiko , Hikosaka Okihide
Published: April 2019

The amygdala is uniquely sensitive to emotional events. However, it is not understood whether and how the amygdala uses such emotional signals to control behavior, especially eye movements. We therefore injected muscimol (GABAAagonist) into the central nucleus of amygdala (CeA) in monkeys. This unilateral temporary inactivation suppressed saccades to contralateral but not ipsilateral targets, resulting in longer latencies, hypometric amplitudes, and slower velocity. During free viewing of movies, gaze was distributed mostly in the ipsilateral hemifield. Moreover, CeA inactivation disrupted the tendency of gaze toward social interaction images, which were normally focused on continuously. Conversely, optogenetic stimulation of CeA facilitated saccades to the contralateral side. These findings suggest that CeA controls spatially selective gaze and attention in emotional contexts, and provide a new framework for understanding psychiatric disorders related to amygdala dysfunction.

Highlights

Central amygdala facilitates contralateral saccades selectively.

Saccade facilitation is related to motivational goals and social interaction.

The amygdala thus controls goal-directed behavior based on emotional contexts.
Morpho-anatomical observations on Phyllanthus of Southwestern Bangladesh with two new records for Bangladesh
Authors: Tuhin Md. Sajjad Hossain , Limon Md. Sharif Hasan
Published: April 2019

An extensive floristic survey was done to annotate Phyllanthus of southwestern Bangladesh from 2015 to 2018. In total, 2189 individuals of Phyllanthus were counted and identified as eight different species (five herbs, two trees and a shrub). All species were examined following both morphological and anatomical methods, based on taxonomic notes. The listed species werePhyllanthus acidus, Phyllanthus amarus, Phyllanthus debilis, Phyllanthus emblica, Phyllanthus niruri, Phyllanthus urinaria, Phyllanthus reticulatusandPhyllanthus virgatus. Among them,Phyllanthus amarusandPhyllanthus debiliswere listed for the first time from Bangladesh during this study period.
A suite of rare microbes interacts with a
dominant, heritable, fungal endophyte to influence
plant trait expression
Authors: Harrison Joshua G. , Beltran Lyra P. , Buerkle C. Alex , Cook Daniel , Gardner Dale R. , Parchman Thomas L. , Poulson Simon R. , Forister Matthew L.
Published: April 2019

Endophytes are microbes that live, for at
least a portion of their life history, within
plant tissues. Endophyte assemblages are often
composed of a few abundant taxa and many
infrequently-observed, rare taxa. The ways in
which most endophytes affect host phenotype are
unknown; however, certain dominant endophytes can
influence plants in ecologically meaningful
ways–including by affecting growth and
contributing to immune responses. In contrast, the
effects of rare endophytes have been unexplored,
and how rare and common endophytes might interact
is also unknown. Here, we manipulate both the
suite of rare foliar endophytes (including both
fungi and bacteria) and Alternaria
fulva–a dominant, vertically-
transmitted fungus–within the fabaceous forb
Astragalus
lentiginosus. We report that rare,
low-biomass endophytes affected host size and
foliar %N, but only when the dominant fungal
endophyte (A. fulva)
was not present. A.
fulva also reduced plant size and
%N, but these deleterious effects on the host
could be offset by a striking antagonism we
observed between this heritable fungus and a
foliar pathogen. These results are unusual in that
they are derived from experimental manipulation in
a non-crop or non-grass system and demonstrate
that interactions among taxa determine the net
effect of endophytic assemblages on their hosts.
We suggest that the myriad infrequently-observed
endophytes within plant leaves may be more than a
collection of uninfluential, commensal organisms,
but instead have meaningful ecological
roles.
Evaluation of the possible association of Body Mass Index and four metabolic gene polymorphisms with longevity in an Italian cohort: a role forAPOE, eNOS, andFTOgene polymorphisms
Authors: Santovito Alfredo , Galli Gabriella , Ruberto Stefano
Published: April 2019

Background

longevity is considered the result of interactions between environmental and genetic factors.

Aim

we investigated the possible association of body mass index and the frequencies ofAPOE, ACE, eNOS, andFTOgene polymorphisms with longevity.

Subjects and Method

1,100 healthy volunteers aged 10-100 were recruited. We genotyped subjects forAPOE, ACE, eNOS, andFTOgene polymorphisms. Data about height and weight were also collected. The sample was split in four age groups: 1-24, 25-49, 50-85 and 86-100.

Results

significant differences were found in BMI values between age groups, with exception of 1-24 with respect to 86-100. A significant decrease of theAPO E4, eNOS 393andFTO Aand allele frequencies was observed in the 86-100 age group with respect to younger groups. ForACEgene, no significant differences were found in the allele frequencies between groups. A similar trend was also observed subdividing the sample in two main age groups: 1-85 and 86-100.

Conclusion

this study provides evidences for a role ofAPOE, eNOS, andFTOgene polymorphisms in longevity. It has been estimated that the number of centenarians worldwide will double each decade until 2100, making population data about gene polymorphisms relevant for further studies about longevity.
Experimental manipulation of selfish genetic elements links genes to microbial community function
Authors: Quistad Steven D. , Doulcier Guilhem , Rainey Paul B.
Published: April 2019

Microbial communities underpin earth’s biological and geochemical processes, but their complexity hampers understanding. Motivated by the challenge of diversity and the need to forge ways of capturing dynamical behaviour connecting genes to function, biologically independent experimental communities comprising hundreds of microbial genera were established from garden compost and propagated on nitrogen-limited minimal medium with cellulose (paper) as sole carbon source. After one year of bi-weekly transfer, communities retained hundreds of genera. To connect genes to function we used a simple experimental manipulation that involved periodic collection of selfish genetic elements (SGEs) from separate communities, followed by pooling and redistribution across communities. The treatment was predicted to promote amplification and dissemination of SGEs and thus horizontal gene transfer (HGT). Confirmation came from comparative metagenomics, which showed substantive movement of ecologically significant genes whose dynamic across space and time could be followed. Enrichment of genes implicated in nitrogen metabolism, and particularly ammonification, prompted biochemical assays that revealed a measurable impact on community function. Our simple experimental strategy offers a conceptually new approach for unravelling dynamical processes affecting microbial community function.
Directional and frequency characteristics of auditory neurons in Culex male mosquitoes
Authors: Lapshin Dmitry N. , Vorontsov Dmitry D.
Published: April 2019

The paired auditory organ of mosquito, the Johnston’s organ (JO), being the receiver of particle velocity component of sound, is directional by its structure. However, to date almost no direct physiological measurements of its directionality was done. In addition, the recent finding on the grouping of the JO auditory neurons into the antiphase pairs demanded confirmation by different methods. Using the vector superposition of the signals produced by two orthogonally oriented speakers, we measured the directional characteristics of individual units as well as their relations in physiologically distinguishable groups – pairs or triplets. The feedback stimulation method allowed to discriminate responses of the two simultaneously recorded units, and to show that they indeed responded in antiphase. We also show that ratios between the individual tuning frequencies in pairs and triplets are non-random and follow the principle of harmonic synchronization, remarkably similar to the one known from the observations of mosquito behavior. Units of different tuning and sensitivity are evenly distributed around the axis of the JO, providing the mosquito with the ability to produce complex auditory behaviors.

Summary statement

Auditory neurons of mosquito are grouped into pairs or triplets, each unit tuned to a specific frequency. Within the pair units respond to opposite directions of the sound. Units of different tuning and sensitivity are evenly distributed around the axis of the Johnston’s organ.
Toward a unified connectomic target for deep brain stimulation in obsessive-compulsive disorder
Authors: Li Ningfei , Baldermann Juan Carlos , Kibleur Astrid , Treu Svenja , Akram Harith , Elias Gavin J.B. , Boutet Alexandre , Lozano Andres M. , Al-Fatly Bassam , Strange Bryan , Barcia Juan , Zrinzo Ludvic , Joyce Eileen , Chabardes Stephan , Visser-Vandewalle Veerle , Polosan Mircea , Kuhn Jens , Kühn Andrea A. , Horn Andreas
Published: April 2019

Multiple surgical targets have been proposed for treating obsessive-compulsive disorder (OCD) with deep brain stimulation (DBS). However, different targets may modulate the same neural network responsible for clinical improvement. Here we analyzed data from four cohorts of OCD patients (N = 50) that underwent DBS to the anterior limb of the internal capsule (ALIC), the nucleus accumbens (NAcc) or the subthalamic nucleus (STN). Fiber tracts that were predominantly connected to electrodes in good or poor DBS responders were isolated from a normative structural connectome and assigned a predictive value. Strikingly, the same fiber bundle was related to treatment response when independently analyzing two large training cohorts that targeted either ALIC or STN. This discriminative tract is a subsection of the ALIC and connects frontal regions (such as the dorsal anterior cingulate, dACC, and ventral prefrontal, vlPFC, cortices to the STN). When informing the tract solely based on one cohort (e.g. ALIC), clinical improvements in the other (e.g. STN) could be significantly predicted, and vice versa. Finally, clinical improvements of eight patients from a third center with electrodes in the NAcc and six patients from a fourth center in which electrodes had been implanted in both STN and ALIC were significantly predicted based on this novel tract-based DBS target. Results suggest a functional role of a limbic hyperdirect pathway that projects from dACC and vlPFC to anteriomedial STN. Obsessive-compulsive symptoms seem to be tractable by modulating the specific bundle isolated here. Our results show that connectivity-derived improvement models can inform clinical improvement across DBS targets, surgeons and centers. The identified tract is now three-dimensionally defined in stereotactic standard space and will be made openly available.