bluuebunny/crossref_metadata_2025 huggingface dataset:
A neurocognitive investigation of the impact of socialising with a robot on empathy for pain
Authors: Cross Emily S. , Riddoch Katie A. , Pratts Jaydan , Titone Simon , Chaudhury Bishakha , Hortensius Ruud
Published: November 2018

To what extent can humans form social relationships with robots? In the present study, we combined functional neuroimaging with a robot socialising intervention to probe the flexibility of empathy, a core component of social relationships, toward robots. Twenty-six individuals underwent identical fMRI sessions before and after being issued a social robot to take home and interact with over the course of a week. While undergoing fMRI, participants observed videos of a human actor or a robot experiencing pain or pleasure in response to electrical stimulation. Repetition suppression of activity in the pain network, a collection of brain regions associated with empathy and emotional responding, was measured to test whether socialising with a social robot leads to greater overlap in neural mechanisms when observing human and robotic agents experiencing pain or pleasure. In contrast to our hypothesis, functional region-of-interest analyses revealed no change in neural overlap for agents after the socialising intervention. Similarly, no increase in activation when observing a robot experiencing pain emerged post-socialising. Whole-brain analysis showed that, before the socialising intervention, superior parietal and early visual regions are sensitive to novel agents, while after socialising, medial temporal regions show agent sensitivity. A region of the inferior parietal lobule was sensitive to novel emotions, but only during the pre-socialising scan session. Together, these findings suggest that a short socialisation intervention with a social robot does not lead to discernible differences in empathy toward the robot, as measured by behavioural or brain responses. We discuss the extent to which longer term socialisation with robots might shape social cognitive processes and ultimately our relationships with these machines.
Insect egg size and shape evolve with ecology, not developmental rate
Authors: Church Samuel H. , Donoughe Seth , de Medeiros Bruno A. S. , Extavour Cassandra G.
Published: November 2018

1

The evolution of organism size is hypothesized to be predicted by a combination of development, morphological constraints, and ecological pressures. However, tests of these predictions using phylogenetic methods have been limited by taxon sampling. To overcome this limitation, we generated a database of more than ten thousand observations of insect egg size and shape from the entomological literature and combined them with published genetic and novel life-history datasets. This enabled us to perform phylogenetic tests of long-standing predictions in size evolution across hexapods. Here we show that across eight orders of magnitude in egg volume variation, the relationship between egg shape and size itself evolves, such that predicted universal patterns of scaling do not adequately explain egg shape diversity. We test the hypothesized relationship between size and development, and show that egg size is not correlated with developmental rate across insects, and that for many insects egg size is not correlated with adult body size either. Finally, we show that the evolution of parasitism and aquatic oviposition both help to explain the diversification of egg size and shape across the insect evolutionary tree. Our study challenges assumptions about the evolutionary constraints on egg morphology, suggesting that where eggs are laid, rather than universal mathematical allometric constants, underlies egg size and shape evolution.
Does juvenile Baltic sturgeon (Acipenser oxyrinchus) smell the enemy?
Authors: Ruiz Maria Cámara , Santo Carlos Espírito , Mai Alfons , Gessner Jorn , Wuertz Sven
Published: November 2018

Atlantic sturgeon (Acipenser oxyrinchus), also known as Baltic sturgeon, is considered extinct in German waters. Fish-rearing for conservation purposes still relies on classical hatchery technology producing fish not well suited for facing life in the wild, lacking behavioural skills such as foraging or anti-predation. Predation is hence a major source of mortality in newly stocked individuals. The aim of this study was to evaluate if naïve Baltic sturgeon juveniles were able to smell and recognize a common predator, sander (Sander lucioperca). Over a period of 30 days, three tanks from each group of Baltic sturgeon were attached to a rearing tank with sander (sander unit) and, as a control, carp (carp unit). Morphology of the dorsal scutes, distribution within the tank, stress (glucose, lactate and cortisol) and gene expression of brain plasticity and cognition were studied in comparison to the control group (carp unit). No significant differences were observed in any of the parameters measured. Thus, we conclude that naïve Baltic sturgeon is not able to innately recognize potential predators and future studies should focus on implementing predator odour together with chemical alarm substances.
Excitatory GABAergic signalling is associated with acquired benzodiazepine resistance in status epilepticus
Authors: Burman Richard J. , Selfe Joshua S. , Lee John Hamin , van den Burg Maurits , Calin Alexandru , Codadu Neela K. , Wright Rebecca , Newey Sarah E. , Parrish R. Ryley , Katz Arieh A. , Wilmshurst Joanne M. , Akerman Colin J. , Trevelyan Andrew J. , Raimondo Joseph V.
Published: November 2018

Status epilepticus (SE) is defined as a state of unrelenting seizure activity. Generalised convulsive SE is associated with a rapidly rising mortality rate, and thus constitutes a medical emergency. Benzodiazepines, which act as positive modulators of chloride (Cl-) permeable GABAA receptors, are indicated as first-line treatment, but this is ineffective in many cases. We found that 48% of children presenting with SE were unresponsive to benzodiazepine treatment, and critically, that the duration of SE at the time of treatment is an important predictor of non-responsiveness. We therefore investigated the cellular mechanisms that underlie acquired benzodiazepine resistance, using rodent organotypic and acute brain slices. Removing Mg2+ ions leads to an evolving pattern of epileptiform activity, and eventually to a persistent state of repetitive discharges that strongly resembles clinical EEG recordings of SE. We found that diazepam loses its antiseizure efficacy and conversely exacerbates epileptiform activity during this stage of SE-like activity. Interestingly, a low concentration of the barbiturate phenobarbital had a similar exacerbating effect on SE-like activity, whilst a high concentration of phenobarbital was effective at reducing or preventing epileptiform discharges. We then show that the persistent SE-like activity is associated with a reduction in GABAA receptor conductance and Cl- extrusion capability. We explored the effect on intraneuronal Cl- using both gramicidin, perforated-patch clamp recordings and Cl- imaging. This showed that during SE-like activity, reduced Cl- extrusion capacity was further exacerbated by activity-dependent Cl- loading, resulting in a persistently high intraneuronal Cl-. Consistent with these results, we found that optogenetic stimulation of GABAergic interneurons in the SE-like state, actually enhanced epileptiform activity in a GABAAR dependent manner. Together our findings describe a novel potential mechanism underlying benzodiazepine-resistant SE, with relevance to how this life-threatening condition should be managed in the clinic.
An agent-based framework for improving wildlife disease surveillance: A case study of chronic wasting disease in Missouri white-tailed deer
Authors: Belsare Aniruddha V. , Gompper Matthew E. , Keller Barbara , Sumners Jason , Hansen Lonnie , Millspaugh Joshua J.
Published: November 2018

Epidemiological surveillance for important wildlife diseases often relies on samples obtained from hunter-harvested animals. A problem, however, is that although convenient and cost-effective, hunter-harvest samples are not representative of the population due to heterogeneities in disease distribution and biased sampling. We developed an agent-based modeling framework that i) simulates a deer population in a user-generated landscape, and ii) uses a snapshot of the in silico deer population to simulate disease prevalence and distribution, harvest effort and sampling as per user-specified parameters. This framework can incorporate real-world heterogeneities in disease distribution, hunter harvest and harvest-based sampling, and therefore can be useful in informing wildlife disease surveillance strategies, specifically to determine population-specific sample sizes necessary for prompt detection of disease. Application of this framework is illustrated using the example of chronic wasting disease (CWD) surveillance in Missouri’s white-tailed deer (Odocoileus virginianus) population. We show how confidence in detecting CWD is grossly overestimated under the unrealistic, but standard, assumptions that sampling effort and disease are randomly and independently distributed. We then provide adjusted sample size recommendations based on more realistic assumptions. These models can be readily adapted to other regions as well as other wildlife disease systems.
Early detection of retinal alteration by visible and near-infrared optical co-herence tomography (vnOCT) in a dexamethasone-induced ocular hypertension mouse model
Authors: Song Weiye , Fu Sipei , Song Shangshang , Zhang Sui , Zhang Lei , Ness Steven , Desai Manishi , Yi Ji
Published: November 2018

Purpose

To apply a novel visible and near-infrared optical coherence tomography (vnOCT) in the dexa-methasone-induced ocular hypertension mouse model, and test the capability of four optical markers, peri-papillary retinal nerve fiber layer (RNFL) thickness, total retinal blood flow, VN ratio and hemoglobin oxygen saturation (sO2), in detecting retinal ganglion cell (RGC) damage in association with ocular hyper-tension.

Methods

Twelve mice (C57BL/6J) were separated into a control (n=6) and a dexamethasone group (n=6) receiving twice daily saline or dexamethasone eye drops, respectively, for 7 weeks. Intraocular pressure (IOP) measurements were taken at baseline and weekly. Optical measurements by vnOCT were longitudinally taken at baseline, 4 weeks and 7 weeks. Following week 7, ex vivo RGC counting was performed by immunostaining.

Results

The dexamethasone group showed a measurable rise in IOP by week 2. Despite the IOP differences between the dexamethasone and control groups, there was not a statistical difference in RNFL thickness or total blood flow over 7 weeks. The dexamethasone group did show an increase in retinal arteriovenous sO2 difference (A-V sO2) that was significant at week 4 and 7. The RNFL VN ratio showed a significant decrease at week 4 and 7 in dexamethasone group associated with a decreased RGC count.

Conclusions

RNFL VN ratio and A-V sO2 are capable of detecting early retinal alterations in the dexamethasone-induced ocular hypertension mouse model. Data analysis suggests VN ratio and A-V sO2 are corralated with RGC loss secondary to ocular hypertension, while being independent of IOP.
Genetic combination risk for schizophrenia
Authors: Oishi Kengo , Niitsu Tomihisa , Kanahara Nobuhisa , Hashimoto Tasuku , Komatsu Hideki , Sasaki Tsuyoshi , Takase Masayuki , Sato Yasunori , Iyo Masaomi
Published: November 2018

Summary Paragraph

Schizophrenia is a highly hereditary mental disease1 related to abnormal dopaminergic activities.2,3 To elucidate the mechanisms underlying schizophrenia’s development, genomic studies have sought to identify the pathogenic genetic polymorphisms. Large-scale genome-wide association studies (GWAS) have reported potential candidate loci that contribute to schizophrenia’s development.4,5 The risk genetic profiles are not yet established. Here we show that the combination of three functional single nucleotide polymorphisms (SNPs) related to the key factors of dopaminergic signaling can be used to predict the risk of schizophrenia’s development, though none of the SNPs is known to be associated by itself. These functional SNPs were reported to demonstrate directional influences in their parent gene activity, perhaps characterizing the integrated properties of dopaminergic signaling. Interestingly, the risk combination presented here included the major genotype as well as the minor polymorphisms, suggesting a possible association of unaffected activities of some dopamine-related genes with the disease development. The phenotype speculated based on the allelic status seemed consistent with the conventional pathophysiological hypotheses, although recently developed predictive methods, such as the polygenic risk score, could miss this potent pathogenic role of carrying a normal genotype by evaluating only minor polymorphisms. Our results demonstrate the presence of a subtype in schizophrenia with the favored genetic background related to dopamine signaling. Our findings indicate the possibility that the combinations could characterize integrated biological functions (including neurotransmission) and therefore identify individuals with a disease risk. The biological microenvironment indicated by the functional SNPs could bring an insight to elucidate the pathogenic mechanisms of developing schizophrenia. Furthermore, we believe that our approach will contribute to the development of innovative means to predict disease risks even for other multi-factorial diseases and then, the following preventive medicine.
Applicability of subcortical EEG metrics of synaptopathy to older listeners with impaired audiograms
Authors: Garrett Markus , Verhulst Sarah
Published: November 2018

Emerging evidence suggests that cochlear synaptopathy is a common feature of sensorineural hearing loss, but it is not known whether electrophysiological metrics targeting synaptopathy in animals can be applied to a broad range of people, such as those with impaired audiograms. This study investigates the applicability of subcortical electrophysiological measures associated with synaptopathy such as auditory brainstem responses (ABRs) and envelope following responses (EFRs) in older participants with high-frequency sloping audiograms. This is important for the development of reliable and sensitive synaptopathy diagnostics in people with normal or impaired outer-hair-cell function. Broadband click-ABRs at different sound pressure levels and EFRs to amplitude-modulated stimuli were recorded, as well as relative EFR and ABR metrics which reduce individual factors such as head size and noise floor level. Most tested metrics showed significant differences between the groups and did not always follow the trends expected from synaptopathy. Audiometric hearing loss and age-related hearing related deficits interacted to affect the electrophysiological metrics and complicated their interpretation in terms of synaptopathy. This study contributes to a better understanding of how electrophysiological synaptopathy metrics differ in ears with healthy and impaired audiograms, which is an important first step towards unravelling the perceptual consequences of synaptopathy.
Uncovering the signaling landscape controlling breast cancer cell migration identifies splicing factor PRPF4B as a metastasis driver
Authors: Fokkelman Michiel , Koedoot Esmee , Rogkoti Vasiliki-Maria , Le Dévédec Sylvia E. , de Sandt Iris van , de Bont Hans , Pont Chantal , Klip Janna E. , Wiemer Erik A.C. , Smid Marcel , Stoilov Peter , Foekens John A. , Martens John W.M. , de Water Bob van
Published: November 2018

Metastasis is the major cause of death in cancer patients and migration of cancer cells from the primary tumor to distant sites is the prerequisite of metastasis formation. Here we applied an imaging-based RNAi phenotypic cell migration screen using two highly migratory basal breast cancer cell lines (Hs578T and MDA-MB-231) to provide a repository for signaling determinants that functionally drive cancer cell migration. We screened ~4,200 individual target genes covering most cell signaling components and discovered 133 and 113 migratory modulators of Hs578T and MDA-MB-231, respectively, of which 43 genes were common denominators of cell migration. Interaction networks of candidate migratory modulators were in common with networks of different clinical breast cancer prognostic and metastasis classifiers. The splicing factors PRPF4B and BUD31 and the transcription factor BPTF were amplified in human primary breast tumors and the expression was associated with metastasis-free survival. Depletion of PRPF4B, BUD31 and BPTF caused primarily down-regulation of genes involved in focal adhesion and ECM-interaction pathways. PRPF4B was essential for triple negative breast cancer cell migration and critical for breast cancer metastasis formation in vivo, making PRPF4B a candidate for further drug development. Our systematic phenotypic screen provides an important repository of candidate metastasis drug targets.
Facial Emotions Perceptions in Young Female Students with High- Level Anxity and Subclinical Panic Disorder. ERP and BEhavioral Study
Authors: Karpova V.Yu. , Mikhailova E.S. , Gerasimenko N.Yu. , Kushnir A.B. , Gordeev S.A. , Alipov N.N.
Published: November 2018

ABSRACT

This study investigated facial emotion processing in non-medicated young students (girls) with panic disorder. 13 young girls with panic disorder and 14 matched healthy controls were recruited. Evoked potential (EP) components P100, N150, and P300 in the posterior areas, and N200, P300, and late negativity were evaluated while the participants recognize angry, fearful, happy, and neutral facial stimuli. The girls with panic disorder showed increased levels of situational anxiety compared to healthy controls. EP demonstrated an increased reactivity to facial expression at sensory stage (P100 component), in particular, on angry faces, that indicates a shift automated attention on threat facial stimuli. The increased reactivity was also found in later processing, corresponding to the P300 component, reflecting an enhanced selective attention to socially important events. In subjects with panic disorder, we also found signs of increased activation in the right temporal area in the P300 time window, and the increased late frontal negativity in 350-450 ms time window. It can be assumed, that altered functional state of the prefrontal regions results in reduced top-down modulating effects on the lower limbic and sensory cortex levels.
Habitat structure drives the evolution of aerial displays in birds
Authors: Menezes João C. T. , Santos Eduardo S. A.
Published: November 2018

Physical properties of the environment may shape signalling traits by determining how effective the signals are in affecting the behaviour of other individuals. Evidence abounds of signalling environment driving the evolution of colours and sounds, but little is known about its influence upon gestural displays. Here, we performed a continent-wide phylogenetic comparative analysis to test the hypothesis that habitat structure drives the evolution of aerial sexual displays in passerine birds. We found that aerial displays are seven times more likely to evolve in open habitats than in forests, likely as a result of physical properties that allow aerial displays to transmit more broadly in open habitats. Our results provide an emblematic example of how environmental factors may help predict the direction of evolution of otherwise unpredictable sexual traits. The broader range of aerial displays in open habitats may also mean that females can sample more males, potentially leading to more intense sexual selection over open-habitat, aerial-displaying males.
Impact of deleterious mutations, sexually antagonistic selection and mode of recombination suppression on transitions between male and female heterogamety
Authors: Saunders Paul A. , Neuenschwander Samuel , Perrin Nicolas
Published: November 2018

Deleterious mutations accumulating on non-recombining Y chromosomes can drive XY to XY turnovers, but are thought to prevent XY to ZW turnovers, because the latter require fixation of the ancestral Y. Using individual-based simulations, we explored whether and how a dominant W allele can spread in a young XY system that gradually accumulates deleterious mutations. We also investigated how sexually antagonistic (SA) polymorphism on the ancestral sex chromosomes, and the mechanism controlling X-Y recombination suppression affect these transitions. In contrast with XY to XY turnovers, XY to ZW turnovers cannot be favored by Y chromosome mutation load. If the arrest of X-Y recombination depends on genotypic sex, transitions are strongly hindered by deleterious mutations, and totally suppressed by very small SA cost, because deleterious mutations and female-detrimental SA alleles would have to fix with the Y. If, however, the arrest of X-Y recombination depends on phenotypic sex, X and Y recombine in XY ZW females, allowing for the purge of Y-linked deleterious mutations and loss of the SA polymorphism, causing XY to ZW turnovers to occur at a neutral rate. We generalize our results to other types of turnovers (e.g., triggered by non-dominant sex-determining mutations) and discuss their empirical relevance.
Neurocognitive and psychiatric markers for addiction: Common vs. specific (endo)phenotypes for opiate and stimulant dependence
Authors: Long Elizabeth C. , Kaneva Radka , Vasilev Georgi , Moeller F. Gerard , Vassileva Jasmin
Published: November 2018

BACKGROUND

The differential utility of neurocognitive impulsivity and externalizing/internalizing traits as putative addiction endophenotypes among individuals dependent on opiates vs. stimulants is unclear. The present study aims to determine: (1) whether neurocognitive impulsivity dimensions and externalizing/internalizing traits are correlated between siblings discordant for opiate and stimulant dependence; and (2) which of these associations are common across substances and which are substance-specific.

METHOD

Pearson correlations between individuals with ‘pure’ heroin and ‘pure’ amphetamine dependence and their unaffected biological siblings (n = 37 heroin sibling pairs; n = 30 amphetamine sibling pairs) were run on 10 neurocognitive measures, 6 externalizing measures, and 5 internalizing measures. Sibling pair effects were further examined using regression.

RESULTS

Siblings discordant for heroin dependence were significantly correlated on delay aversion on the Cambridge Gambling Task, risk-taking on the Balloon Analogue Risk Task, sensation seeking, and hopelessness. Siblings discordant for amphetamine dependence were significantly correlated on quality of decision-making on the Cambridge Gambling Task, discriminability on the Immediate Memory Task, commission errors on the Go/No-Go Task, trait impulsivity, ADHD, and anxiety sensitivity.

CONCLUSIONS

Dimensions of impulsivity and externalizing/internalizing traits appear to aggregate among siblings discordant for substance dependence. Risk-taking propensity, sensation seeking, and hopelessness were specific for heroin sibling pairs. Motor/action impulsivity and trait impulsivity were specific to amphetamine sibling pairs. Decisional/choice impulsivity was common across both heroin and amphetamine sibling pairs. These findings provide preliminary evidence for the utility of neurocognitive impulsivity and externalizing/internalizing traits as candidate endophenotypes for substance dependence in general and for substance-specific dependencies.
The transcriptional landscape of cortical interneurons underlies in-vivo brain function and schizophrenia risk
Authors: Anderson Kevin M , Collins Meghan A , Chin Rowena , Ge Tian , Rosenberg Monica D , Holmes Avram J
Published: November 2018

Inhibitory interneurons orchestrate information flow across cortex and are implicated in psychiatric illness. Although classes of interneurons have unique functional properties and spatial distributions throughout the brain, the relative influence of interneuron subtypes on brain function, cortical specialization, and illness risk remains elusive. Here, we demonstrate stereotyped organizational properties of somatostatin and parvalbumin related transcripts within human and non-human primates. Interneuron spatial distributions recapitulate cortico-striato-thalamic functional networks and track regional differences in functional MRI signal amplitude. In the general population (n=9,627), parvalbumin-linked genes account for an enriched proportion of genome-wide heritable variance in in-vivo functional MRI signal amplitude. This relationship is spatially dependent, following the topographic organization of parvalbumin expression in independent post-mortem brain tissue. Finally, genetic risk for schizophrenia is enriched among interneuron-linked genes and predictive of cortical signal amplitude in parvalbumin-biased regions. These data indicate that the molecular genetic basis of resting-state brain function across cortex is shaped by the spatial distribution of interneuron-related transcripts and underlies individual differences in risk for schizophrenia.

Key Findings

Spatial distributions of somatostatin (SST) and parvalbumin (PVALB) are negatively correlated in mature human and non-human primate cortex, paralleling patterns observed in utero.

SST and PVALB are differentially expressed within distinct limbic and somato/motor cortico-striato-thalamic networks, respectively.

In-vivo resting-state signal amplitude is heritable in the general population and tracks relative SST/PVALB expression across cortex.

Single-nucleotide polymorphisms tied to PVALB-related genes account for an enriched proportion of the heritable variance in resting-state signal amplitude.

PVALB-mediated heritability of resting-state signal amplitude in the general population is spatially heterogeneous, mirroring the cortical expression of PVALB in independent post-mortem brain tissue.

Polygenic risk for schizophrenia is enriched among interneuron-linked genes and predicts resting-state signal amplitude in a manner that also follows the cortical expression of PVALB.
Habitat loss-induced tipping points in metapopulations with facilitation
Authors: Sardanyés Josep , Piñero Jordi , Solé Ricard
Published: November 2018

Habitat loss is known to pervade extinction thresholds in metapopulations. Such thresholds result from a loss of stability that can eventually lead to collapse. Several models have been developed to understand the nature of these transitions and how are they affected by the locality of interactions, fluctuations, or external drivers. Most models consider the impact of grazing or aridity as a control parameter that can trigger sudden shifts, once critical values are reached. Others explore instead the role played by habitat loss and fragmentation. Here we consider a minimal model incorporating facilitation along with habitat destruction, with the aim of understanding how local cooperation and habitat loss interact with each other. An explicit mathematical model is derived, along with a spatially explicit simulation model. It is found that a catastrophic shift is expected for increasing levels of habitat loss, but the breakpoint dynamics becomes continuous when dispersal is local. Under these conditions, spatial patchiness is found and the qualitative change from discontinuous to continuous results from a universal behaviour found in a broad class of nonlinear ecological systems (Weissmann and Shnerb, 2014; Martinet al.PNAS (2015) E1828-E1836). Our results suggest that species exhibiting facilitation and displaying short-range dispersal will be markedly more capable of dealing with habitat destruction, also avoiding catastrophic tipping points.
Both Fallopian Tube and Ovarian Surface Epithelium Can Act as Cell-of-Origin for High Grade Serous Ovarian Carcinoma
Authors: Zhang Shuang , Zhang Tao , Dolgalev Igor , Ran Hao , Levine Douglas A. , Neel Benjamin G.
Published: November 2018

The cell-of-origin of high grade serous ovarian carcinoma (HGSOC) remains controversial, with fallopian tube epithelium (FTE) and ovarian surface epithelium (OSE) each suggested as candidates. Here, by using genetically engineered mouse models and novel organoid systems, we assessed the tumor-forming capacity and properties of FTE and OSE harboring the same oncogenic abnormalities. Combined RB family inactivation (via T121 expression) and Tp53 mutation in Pax8+ FTE caused transformation to Serous Tubal Intraepithelial Carcinoma (STIC), which rapidly metastasized to the ovarian surface. This mouse model was recapitulated by FTE organoids, which, upon orthotopic injection, generated widely metastatic HGSOC. The same genetic lesions in Lgr5+ OSE cells or organoids also caused metastatic HGSOC, although with longer latency and lower penetrance. Comparative transcriptome analysis was consistent with different human HGSOCs arising from FTE and OSE. Furthermore, FTE- and OSE-derived organoids showed differential sensitivity to HGSOC chemotherapeutics. Our results comport with a dualistic origin for HGSOC and suggest the cell-of-origin could influence therapeutic response.

SIGNIFICANCE

The cell-of-origin for high grade serous ovarian carcinoma (HGSOC) has been controversial. By generating novel GEMMs and organoid models with the same oncogenic defects, we demonstrate that HGSOC can originate from either fallopian tube epithelium (FTE) or ovarian surface epithelium (OSE). Importantly, FTE- and OSE-derived tumors differ significantly in biologic properties.
The Hi-Culfite assay reveals relationships between chromatin contacts and DNA methylation state
Authors: Stamenova Elena K. , Durand Neva C. , Dudchenko Olga , Shamim Muhammad S. , Huang Su-Chen , Jiang Yiqun , Bochkov Ivan D. , Rao Suhas S. P. , Lander Eric S. , Gnirke Andreas , Aiden Erez Lieberman
Published: November 2018

Hi-Culfite, a protocol combining Hi-C and whole-genome bisulfite sequencing (WGBS), determines chromatin contacts and DNA methylation simultaneously. Hi-Culfite also reveals relationships that cannot be seen when the two assays are performed separately. For instance, we show that loci associated with open chromatin exhibit context-sensitive methylation: when their spatial neighbors lie in closed chromatin, they are much more likely to be methylated.
A schizophrenia risk gene, NRGN, bidirectionally modulates synaptic plasticity via regulating the neuronal phosphoproteome
Authors: Hwang Hongik , Szucs Matthew J. , Ding Lei J. , Allen Andrew , Haensgen Henny , Gao Fan , Andrade Arturo , Pan Jennifer Q. , Carr Steven A. , Ahmad Rushdy , Xu Weifeng
Published: November 2018

NRGN is a schizophrenia risk gene identified in recent genetic studies, encoding a small neuronal protein, neurogranin (Ng). Individuals carrying a risk variant of NRGN showed decreased hippocampal activation during contextual fear conditioning. Furthermore, the expression of Ng was reduced in the post-mortem brains of schizophrenic patients. Using the mouse model, we found that the translation of Ng in hippocampus is rapidly increased in response to novel context exposure, and this up-regulation is required for encoding contextual memory. The extent and degree of the effect that altered Ng expression has on neuronal cellular functions are largely unknown. Here, we found that Ng bidirectionally regulates synaptic plasticity in the hippocampus. Elevated Ng levels facilitated long-term potentiation (LTP), whereas decreased Ng levels impaired LTP. Quantitative phosphoproteomic analysis revealed that decreasing Ng caused a significant shift in the phosphorylation status of postsynaptic density proteins, highlighting clusters of schizophrenia- and autism-related genes. In particular, decreasing Ng led to the hypo-phosphorylation of NMDAR subunit Grin2A at newly identified sites, resulting in accelerated decay of NMDAR-mediated channel currents. blocking protein phosphatase PP2B activity rescued the accelerated synaptic NMDAR current decay and the impairment of LTP caused by decreased Ng levels, suggesting that enhanced synaptic PP2B activity led to the deficits. Taken together, our work suggests that altered Ng levels under pathological conditions affect the phosphorylation status of neuronal proteins by tuning PP2B activity and thus the induction of synaptic plasticity, revealing a novel mechanistic link of a schizophrenia risk gene to cognitive deficits.
Bedsect: An integrated web server application to perform intersection, visualization and functional annotation of genomic regions from multiple datasets
Authors: Mishra Gyan Prakash , Ghosh Arup , Jha Atimukta , Raghav Sunil Kumar
Published: November 2018

A large number of genomic regions captured during next generation sequencing (NGS) data analyses are generally overlapped to answer a variety of biological questions. Though several command-line tools are available to perform such analysis, there is lack of a comprehensive web server application to perform the genomic region intersections from multiple datasets, to generate a plot for the subsets of the overlapped regions and to perform integrated functional annotation. To address this gap, we have developed a user-friendly integrated web server application i.e. Bedsect, where users can upload genomic regions from multiple datasets without any file number limitation and perform intersection analysis along with visualization of the intersection regions as UpSet and Correlation plot using integrated Shiny application. Bedsect also integrates GREAT for functional annotation, gene ontology, and biological pathways enrichment analysis from identified unique as well as intersected genomic regions. These genomic regions can be further uploaded in the UCSC genome browser for visualization of the results as custom tracks directly from the tool. Bedsect is available at http://imgsb.org/bedsect/.
Proof of concept: Malaria rapid diagnostic tests and massively parallel sequencing for surveillance of molecular markers of antimalarial resistance in Bissau, Guinea-Bissau during 2014-2017
Authors: Nag Sidsel , Ursing Johan , Rodrigues Amabelia , Crespo Marina , Krogsgaard Camilla , Lund Ole , Aarestrup Frank M. , Alifrangis Michael , Kofoed PouL-Erik
Published: November 2018

Real-time and large-scale surveillance of molecular markers of antimalarial drug resistance is a potential method of resistance monitoring, to complement therapeutic efficacy studies in settings where the latter are logistically challenging. This study investigates whether routinely used malaria rapid diagnostic tests (RDTs) can be used for massive parallel amplicon sequencing. RDTs used for malaria diagnosis were routinely collected together with patient age and sex between 2014 and 2017, from two health centres in Bissau, Guinea-Bissau. A subset of positive RDTs (n=2,184) were tested for Plasmodium DNA content. Those containing sufficient Plasmodium DNA (n=1,390) were used for library preparation, consisting of amplification of gene fragments from pfcrt, pfmdr1, pfdhfr, pfdhps and pfK13. A total of 5532 gene fragments were successfully analysed on a single Illumina Miseq flow cell. Pre-screening of samples for Plasmodium DNA content proved necessary and the nested PCR protocol applied for library preparation varied notably in PCR-positivity from 13-87%. We found a high frequency of the pfmdr1 codon 86N at 88%-97%, a significant decrease of the pfcrt wildtype CVMNK haplotype and elevated levels of the pfdhfr/pfdhps quadruple mutant ranging from 33%-51% between 2014-2017. No polymorphisms indicating artemisinin tolerance were discovered. Lastly, the demographic data indicate a large proportion of young adults (66%, interquartile range 11-28 years) presenting with P. falciparum infections. With some caution, our findings suggest that routine collection of RDTs could facilitate large-scale molecular surveillance of antimalarial resistance.

Importance (word count: 147)

Continuous spread and repeated emergence of Plasmodium falciparum parasites resistant towards one or more antimalarials represents an enormous threat to current treatment efficacy levels, especially in sub-Saharan Africa, where 90% of malaria infections occur. In order to prevent substantial treatment failure, it is therefore recommended to monitor treatment efficacy every 2-3 years. Therapeutic efficacy studies, however, can present insurmountable logistical and financial challenges in some settings in sub-Saharan Africa. Molecular surveillance of antimalarial resistance is therefore an important proxy for treatment efficacy. However, the scale by which such studies can be performed depends on the development of high-throughput protocols and the accessibility of samples. If RDTs can be used in the high-throughput protocols available with Next Generation Sequencing (NGS)-technology, surveillance can be performed efficiently for any setting in which RDTs are already used for malaria diagnosis. The majority of settings in sub-Saharan Africa have access to RDTs.
The novelDblhomology/BAR domain protein, MsgA, ofTalaromyces marneffeiregulates yeast morphogenesis during growth inside host cells
Authors: Weerasinghe Harshini , Bugeja Hayley E. , Andrianopoulos Alex
Published: November 2018

Microbial pathogens have evolved many strategies to evade recognition by the host immune system, including the use of phagocytic cells as a niche within which to proliferate. Dimorphic pathogenic fungi employ an induced morphogenetic transition, switching from multicellular hyphae to unicellular yeast that are more compatible with intracellular growth. A switch to mammalian host body temperature (37°C) is a key trigger for the dimorphic switch. This study describes a novel gene,msgA, from the dimorphic fungal pathogenTalaromyces marneffeithat controls cell morphology in response to host cues rather than temperature. ThemsgAgene is upregulated during murine macrophage infection, and deletion results in aberrant yeast morphology solely during growth inside macrophages. MsgA contains a Dbl homology domain, and aBin,Amphiphysin,Rvs (BAR) domain instead of a Plekstrin homology domain typically associated with guanine nucleotide exchange factors (GEFs). The BAR domain is crucial in maintaining yeast morphology and cellular localisation during infection. The data suggests that MsgA does not act as a canonical GEF during macrophage infection and identifies a temperature independent pathway inT.marneffeithat controls intracellular yeast morphogenesis.
Mechanism of action of methotrexate against Zika virus
Authors: Beck Sungjun , Bernatchez Jean A. , Zhu Zhe , Oliveira Michelli F. , Smith Davey M. , Siqueira-Neto Jair L.
Published: November 2018

Zika virus (ZIKV), which is associated with microcephaly in infants and Guillain-Barré syndrome, reemerged as a serious public health threat in Latin America in recent years. Previous high-throughput screening (HTS) campaigns have revealed several potential hit molecules against ZIKV, including methotrexate (MTX), which is clinically used as an anti-cancer chemotherapy and anti-rheumatoid agent. We studied the mechanism of action of MTX against ZIKV in relation to its inhibition of dihydrofolate reductase (DHFR)in vitrousing Vero and human neural stem cells (hNSCs). As expected, an antiviral effect for MTX against ZIKV was observed, showing up to ten-fold decrease in virus titer during MTX treatment. We also observed that addition of leucovorin (a downstream metabolite of DHFR pathway) rescued the ZIKV replication impaired by MTX treatment in ZIKV-infected cells, explaining the antiviral effect of MTX through inhibition of DHFR. We also found that addition of adenosine to ZIKV-infected cells was able to rescue ZIKV replication inhibited by MTX, suggesting that restriction ofde novosynthesis adenosine triphosphate (ATP) pools suppresses viral replication. These results confirm that the DFHR pathway can be targeted to inhibit replication of ZIKV, similar to other published results showing this effect in related flaviviruses.
TheDrosophila fusselgene is required for bitter gustatory neuron differentiation acting within an Rpd3 dependent chromatin modifying complex
Authors: Rass Mathias , Oestreich Svenja , Guetter Severin , Fischer Susanne , Schneuwly Stephan
Published: November 2018

Members of the Ski/Sno protein family are classified as proto-oncogenes and act as negative regulators of the TGF-ß/BMP-pathways in vertebrates and invertebrates. A newly identified member of this protein family isfussel(fuss), theDrosophilahomologue of the humanfunctional Smad suppressing elements(fussel-15andfussel-18). We and others have shown that Fuss interacts with SMAD4 and that overexpression leads to a strong inhibition of Dpp signaling. However, to be able to characterize the endogenous Fuss function inDrosophila melanogaster,we have generated a number of state of the art tools including anti-Fuss antibodies, specificfuss-Gal4 lines andfussmutant fly lines via the CRISPR/Cas9 system. Fuss is a predominantly nuclear, postmitotic protein, mainly expressed in interneurons andfussmutants are fully viable without any obvious developmental phenotype. To identify potential target genes or cells affected infussmutants, we conducted targeted DamID experiments in adult flies, which revealed the function offussin bitter gustatory neurons. We fully characterizedfussexpression in the adult proboscis and by using food choice assays we were able to show thatfussmutants display defects in detecting bitter compounds. This correlated with a reduction of gustatory receptor gene expression (Gr33a, Gr66a, Gr93a) providing a molecular link to the behavioral phenotype. In addition, Fuss interacts with Rpd3, and downregulation ofrpd3in gustatory neurons phenocopies the loss of Fuss expression. Surprisingly, there is no colocalization of Fuss with phosphorylated Mad in the larval central nervous system, excluding a direct involvement of Fuss in Dpp/BMP signaling.

Here we provide a first and exciting link of Fuss function in gustatory bitter neurons. Although gustatory receptors have been well characterized, little is known regarding the differentiation and maturation of gustatory neurons. This work therefore reveals Fuss as a pivotal element for the proper differentiation of bitter gustatory neurons acting within a chromatin modifying complex.
Random Tanglegram Partitions (Random TaPas): An Alexandrian Approach to the Cophylogenetic Gordian Knot
Authors: Balbuena Juan Antonio , Pérez-Escobar Óscar Alejandro , Llopis-Belenguer Cristina , Blasco-Costa Isabel
Published: November 2018

Symbiosis is a key driver of evolutionary novelty and ecological diversity, but our understanding of how macroevolutionary processes originate extant symbiotic associations is still very incomplete. Cophylogenetic tools are used to assess the congruence between the phylogenies of two groups of organisms related by extant associations. If phylogenetic congruence is higher than expected by chance, we conclude that there is cophylogenetic signal in the system under study. However, how to quantify cophylogenetic signal is still an open issue. We present a novel approach, Random Tanglegram Partitions (Random TaPas) that applies a given global-fit method to random partial tanglegrams of a fixed size to identify the associations, terminals and nodes that maximize phylogenetic congruence. By means of simulations, we show that the output value produced is inversely proportional to the number and proportion of cospeciation events employed to build simulated tanglegrams. In addition, with time-calibrated trees, Random TaPas is also efficient at distinguishing cospeciation from pseudocospeciation. Random TaPas can handle large tanglegrams in affordable computational time and incorporates phylogenetic uncertainty in the analyses. We demonstrate its application with two real examples: Passerine birds and their feather mites, and orchids and bee pollinators. In both systems, Random TaPas revealed low cophylogenetic signal, but mapping its variation onto the tanglegram pointed to two different coevolutionary processes. We suggest that the recursive partitioning of the tanglegram buffers the effect of phylogenetic nonindependence occurring in current global-fit methods and therefore Random TaPas is more reliable than regular global-fit methods to identify host-symbiont associations that contribute most to cophylogenetic signal. Random TaPas can be implemented in the public-domain statistical software R with scripts provided herein. A User’s Guide is also available at GitHub.
Yeast-to-hypha transition ofSchizosaccharomyces japonicusin response to natural stimuli
Authors: Kinnaer Cassandre , Dudin Omaya , Martin Sophie G
Published: November 2018

Many fungal species are dimorphic, exhibiting both unicellular yeast-like and filamentous forms.Schizosaccharomyces japonicus, a member of the fission yeast clade, is one such dimorphic fungus. Here, we first identify fruit extracts as natural, stress-free, starvation-independent inducers of filamentation, which we use to describe the properties of the dimorphic switch. During the yeast-to-hypha transition, the cell evolves from a bipolar to a unipolar system with 10-fold accelerated polarized growth but constant width, vacuoles segregated to the non-growing half of the cell, and hyper-lengthening of the cell. We demonstrate unusual features ofS. japonicushyphae: these cells lack a Spitzenkörper, a vesicle distribution center at the hyphal tip, but display more rapid cytoskeleton-based transport than the yeast form, with actin cables being essential for the transition.S. japonicushyphae also remain mononuclear and undergo complete cell divisions, which are highly asymmetric: one daughter cell inherits the vacuole, the other the growing tip. We show these elongated cells scale their nuclear size, spindle length and elongation rates but display altered division size controls. This establishesS. japonicusas a unique system that switches between symmetric and asymmetric modes of growth and division.
Identification of biomarkers and pathways to identify novel therapeutic targets in Alzheimer’s disease: Insights from a systems biomedicine perspective
Authors: Rahman Md. Rezanur , Islam Tania , Zaman Toyfiquz , Shahjaman Md. , Karim Md. Rezaul , Huq Fazlul , Quinn Julian M.W. , Holsinger R. M. Damian , Moni Mohammad Ali
Published: November 2018

Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by the accumulation of amyloid plaques and neurofibrillary tangles in the brain. However, there are no peripheral biomarkers available that can detect AD onset. This study aimed to identify such AD biomarkers through an integrative analysis of blood cell gene expression data. We used two microarray datasets (GSE4226 and GSE4229) comparing blood cell transcriptomes of AD patients and matched controls to identify differentially expressed genes (DEGs). Geneset and protein overrepresentation analysis, protein-protein interaction (PPI), DEGs-Transcription Factor interactions, DEGs-MicroRNAs interactions, protein-drug interactions, and protein subcellular localizations analyses were performed on DEGs common to the datasets. We identified 25 common DEGs between the two datasets. Integration of genome scale transcriptome datasets with biomolecular networks revealed hub genes (TUBB, ATF3, NOL6, UQCRC1, SND1, CASP2, BTF3, INPP5K, VCAM1, and CSTF1), common transcription factors (FOXC1, ZNF3, GEMIN7, and SMG9) and miRNAs (mir-20a-5p, mir-93-5p, mir-16-5p, let-7b-5p, mir-708-5p, mir-24-3p, mir-26b-5p, mir-17-5p, mir-4270, and mir-4441). These included 8 previously identified AD markers (BTF3, VCAM, FOXC1, mir-26b-5p, mir-20a-5p, mir-93-5p, let-7b-5p, mir-24-3p) and 13 novel AD biomarkers. Evaluation of histone modification revealed that hub genes and transcription factors possess several histone modification sites associated with AD. Protein-drug interactions revealed 10 compounds that affect the identified AD candidate markers, including anti-neoplastic agents (Vinorelbine, Vincristine, Vinblastine, Epothilone D, Epothilone B, CYT997, and ZEN-012), a dermatological (Podofilox) and an immunosuppressive agent (Colchicine). The subcellular localization of markers varied, including nuclear, plasma membrane and cytosolic proteins. This study identified blood-cell derived molecular biomarker signatures that might be useful as peripheral biomarkers in AD. This study also identified drug and epigenetic data associated with these molecules that may be useful in designing therapeutic approaches to ameliorate AD.