bluuebunny/crossref_metadata_2025 huggingface dataset:
Protective microbe enhances colonisation of a novel host species by modifying immune gene expression
Authors: Ford Suzanne A. , King Kayla C.
Published: December 2019

Microbes that protect against infection inhabit hosts across the tree of life. It is unclear whether many protective microbes use or reduce the need for a host immune response, or how the immune system reacts when these microbes newly encounter a host species naturally and as part of a biocontrol strategy. We sequenced the transcriptome of a host (Caenorhabditis elegans) following its interaction with a non-native bacterium (Enterococcus faecalis) that has protective traits against the pathogen, Staphylococcus aureus. We show that microbe-mediated protection caused the differential expression of 1,557 genes, including the upregulation of many immune gene families conserved across the animal kingdom (e.g. lysozymes and c-type lectins). We found that this modulation of the host’s immune response was beneficial for both the protective microbe and the host. Given E. faecalis’ increased ability to resist lysozyme activity compared to S. aureus, our results indicate that the protective microbe could more easily invade and protect infected hosts by upregulating lysozyme genes. These results suggest that a protective microbe can exploit the host immune system even when introduced into a novel species. Microbes that protect via the host immune response in this way should favour continued investment into host immunity and avoid the evolution of host dependence.

Author summary

Organisms can be protected from infectious disease by the microbes they house. It is unclear, however, whether protective microbes affect the host immune response to infection, particularly in the early stages of symbiosis. In this study, we investigated the role of the host immune system in a novel protective interaction. We examined gene expression in a nematode after colonisation by a non-native microbe capable of suppressing the pathogen Staphylococcus aureus. The protective microbe altered the host immune response to infection in a way that it could exploit. By causing the host to increase the production of antimicrobials to which it itself is relatively resistant, the protective microbe was better able to colonise and defend infected hosts. These results indicate that protective microbes introduced into new host species can take advantage of the host immune system. Such a mechanism at the beginning of a protective symbiosis, formed either naturally or as part of a biocontrol strategy, could ensure continued investment in host-based defences over evolutionary time.
Sterols as dietary markers forDrosophila melanogaster
Authors: Knittelfelder Oskar , Prince Elodie , Sales Susanne , Fritzsche Eric , Wöhner Thomas , Brankatschk Marko , Shevchenko Andrej
Published: December 2019

During cold acclimation fruit flies switch their feeding from yeast to plant food, however there are no robust markers to monitor it in the wild.Drosophila melanogasteris a sterol auxotroph and relies on dietary sterols to produce lipid membranes, lipoproteins and molting hormones. We employed shotgun lipidomics to quantify eight major food sterols in total extracts of heads, female and male genital tracts of adult flies. We found that their sterol composition is dynamic and reflective of flies diet in an organ-specific manner. Season-dependent changes observed in the organs of wild-living flies suggested that the molar ratio between yeast (ergosterol, zymosterol) and plant (sitosterol, stigmasterol) sterols is a quantifiable, generic and unequivocal marker of their feeding behavior, including cold acclimation. It provides technically simpler and more contrast readout compared to the full lipidome analysis and is suitable for ecological and environmental population-based studies.
Methylenetetrahydrofolate reductase deficiency alters cellular response after ischemic stroke in male mice
Authors: Abato Jamie E. , Moftah Mahira , Cron Greg O. , Smith Patrice D. , Jadavji Nafisa M.
Published: December 2019

Objective

Elevated homocysteine concentrations are a risk factor for stroke. A common genetic polymorphism in methylenetetrahydrofolate reductase (MTHFR 677 C➔T) results in elevated levels of homocysteine. MTHFR plays a critical role in the synthesis of S-adenosylmethionine (SAM), a global methyl donor. Our previous work has demonstrated that Mthfr+/− mice, which model the MTHFR polymorphism in humans, are more vulnerable to ischemic damage. The aim of this study was to investigate the cellular mechanisms by which the MTHFR-deficiency changes the brain in the context of ischemic stroke injury.

Methods

In the present study, three-month-old male Mthfr+/− and wild-type littermate mice were subjected to photothrombosis (PT) damage. Four weeks after PT damage, animals were tested on behavioral tasks, in vivo imaging was performed using T2-weighted MRI, and brain tissue was collected.

Results

Mthfr+/− animals used their non-impaired forepaw more during to explore the cylinder and had a larger damage volume compared to wild-type littermates. In brain tissue of Mthfr+/− mice methionine adenosyltransferase II alpha (MAT2A) protein levels were decreased within the damage hemisphere and increased levels in hypoxia induced factor 1 alpha (HIF-1α) in non-damage hemisphere. There was an increased antioxidant response in the damage site as indicated by higher levels of nuclear factor erythroid 2-related factor 2 (Nrf2) and superoxide dismutase 2 (SOD2).

Conclusions

Our results suggest that Mthfr+/− mice are more vulnerable to PT-induced stroke damage through regulation of the cellular response. The increased antioxidant response we observed may be compensatory to the damage amount.
Further evidence of increased human Herpesvirus in Alzheimer’s disease
Authors: Readhead Ben , Haure-Mirande Jean-Vianney , Ehrlich Michelle E. , Gandy Sam , Dudley Joel T.
Published: December 2019

The recent coordination of scientific and political efforts within the field of Alzheimer’s disease (AD) research coupled with the rapid evolution of molecular profiling technologies has enabled the generation of unprecedented repositories of biological sequence data available for investigation by the scientific community. Next-generation sequences (NGS) represent complex readouts of cellular transcriptomic and genomic states, and hold the potential to illuminate disease biology via unexpected applications of collected data. We recently reported a multiomic study of the Alzheimer’s associated brain virome, leveraging NGS data to understand the potential relevance of viral activity to AD. We observed increased abundance of human herpesvirus 6A (HHV-6A), HHV-7, and herpes simplex virus 1 (HSV-1) genomes in banked postmortem brains from subjects with AD compared with controls. These results were replicated in two additional, independent and geographically dispersed cohorts. Although these findings might be of general interest to the field, such analyses present novel methodological challenges that have not been well characterized. The viral abundances that we detected were generally quite low, and, in many samples, no virome was detected. We sought to understand whether such sparsity might be associated with the spurious detection of differential abundance. Herein, we employ a simulation approach, which indicates that sparsity in abundance actually biases against the detection of significant differences between AD and control subjects. We also report new results based on previously unpublished whole genome sequences that show increases in both abundance and prevalence of HHV-6A in AD, consistent with our previously reported results. These findings, as well as reports from many other groups employing a variety of approaches, support the dedication of a coordinated effort toward a comprehensive characterization of the microbiome of the brain affected by AD. Such studies should advance our understanding of the potential clinical relevance of these observations.
Genome-wide Association Study of Pediatric Obsessive-Compulsive Traits: Shared Genetic Risk between Traits and Disorder
Authors: Burton Christie L. , Lemire Mathieu , Xiao Bowei , Corfield Elizabeth C. , Erdman Lauren , Bralten Janita , Poelmans Geert , Yu Dongmei , Shaheen S-M , Goodale Tara ,   OCD Working Group of the Psychiatric Genomics Consortium, Soreni Noam , Hanna Gregory L. , Fitzgerald Kate D. , Rosenberg David , Nestadt Gerry , Paterson Andrew D. , Strug Lisa , Schachar Russell J. , Crosbie Jennifer , Arnold Paul D.
Published: December 2019

Objective

To identify genetic variants associated with obsessive-compulsive (OC) traits and test for sharing of genetic risks between OC traits and obsessive-compulsive disorder (OCD).

Methods

We conducted a genome-wide association analysis of OC traits using the Toronto Obsessive-Compulsive Scale (TOCS) in 5018 unrelated Caucasian children and adolescents from the community (Spit for Science sample). We tested the hypothesis that genetic variants associated with OC traits from the community would be associated with clinical OCD using a meta-analysis of three OCD case-controls samples (cases=3384, controls=8363). Shared genetic risk was examined between OC traits and OCD in the respective samples using polygenic risk score and genetic correlation analyses.

Results

A locus tagged by rs7856850 in an intron ofPTPRD(protein tyrosine phosphatase δ) was significantly associated with OC traits at the genome-wide significance level (p=2.48×10−8). The rs7856850 locus was also associated with OCD in a meta-analysis of three independent OCD case/control genome-wide datasets (p=0.0069). Polygenic risk scores derived from OC traits were significantly associated with OCD in a sample of childhood-onset OCD and vice versa (p’s<0.01). OC traits were highly but not significantly genetically correlated with OCD (rg=0.83,p=0.07).

Conclusions

We report the first validated genome-wide significant variant for OC traits. OC traits measured in the community sample shared genetic risk with OCD case/control status. Our results demonstrate the importance of the type of measure used to measure traits as well as the feasibility and power of using trait-based approaches in community samples for genetic discovery.
Multi-Model and Network Inference Based on Ensemble Estimates: Avoiding the Madness of Crowds
Authors: Stumpf Michael P.H.
Published: December 2019

Recent progress in theoretical systems biology, applied mathematics and computational statistics allows us to compare quantitatively the performance of different candidate models at describing a particular biological system. Model selection has been applied with great success to problems where a small number — typically less than 10 — of models are compared, but recently studies have started to consider thousands and even millions of candidate models. Often, however, we are left with sets of models that are compatible with the data, and then we can use ensembles of models to make predictions. These ensembles can have very desirable characteristics, but as I show here are not guaranteed to improve on individual estimators or predictors. I will show in the cases of model selection and network inference when we can trust ensembles, and when we should be cautious. The analyses suggests that the careful construction of an ensemble – choosing good predictors – is of paramount importance, more than had perhaps been realised before: merely adding different methods does not suffice. The success of ensemble network inference methods is also shown to rest on their ability to suppress false-positive results. A Jupyter notebook which allows carrying out an assessment of ensemble estimators is provided.
Perceptual decisions are biased toward relevant prior choices
Authors: Feigin Helen , Baror Shira , Bar Moshe , Zaidel Adam
Published: December 2019

Perceptual decisions are biased by recent perceptual history, a phenomenon termed 'serial dependence.' Using a visual location discrimination task, we investigated what aspects of perceptual decisions lead to serial dependence, and disambiguated the influences of low-level sensory information, prior choices and motor actions on subsequent perceptual decisions. Following several biased (prior) location discriminations, subsequent (test) discriminations were biased toward the prior choices, even when reported via different motor actions, and when prior and test stimuli differed in color. By contrast, biased discriminations about an irrelevant stimulus feature did not substantially influence subsequent location discriminations. Additionally, biased stimulus locations, when color was discriminated, no longer substantially influenced subsequent location decisions. Hence, the degree of relevance between prior and subsequent perceptual decisions is a key factor for serial dependence. This suggests that serial-dependence reflects a high-level mechanism by which the brain predicts and interprets incoming sensory information in accordance with relevant prior choices.
Multiversal SpaceTime (MSpaceTime) Not Neural Network as Source of Intelligence in Generalized Quantum Mechanics, Extended General Relativity, Darwin Dynamics for Artificial Super Intelligence Synthesis
Authors: Zhang Yang
Published: December 2019

From Synthesis perspective, whether Logic Synthesis, Physical Synthesis, Chemical Synthesis, or Biological Synthesis, Physical Geometry such as Universal Geometry and Quantum Geometry, and Biological Geometry like Conformal Geometry supported by Tensors and Manifolds, are the outcome of physical laws and biological laws in modeling non-linear physical and biological dynamics as opposed to traditional partial differential/difference equation way. We discover that Multiversal SpaceTime instead of Neural Network, governing physical and biological world at macroscopic and microscopic level, is the ultimate source of intelligence. With that we propose Multiversal Synthesis-based Artificial Design Automation (ADA), a bio-physical inspired model based on Multiverse in Darwin Dynamics, Generalized Quantum Mechanics, and Extended General Relativity, for Artificial Super Intelligence (ASI) implementation. Based on Schrodinger Equation of Quantum Mechanics, we generalize the 4-Dimensional Hilbert Space based Discrete Quantum SpaceTime to N-Dimensional (1 ≪N<M, with M is limited by Planck Length) Hilbert Space based Discrete MSpaceTime as part of MSpaceTime, in modeling both Micro-Environment Intelligence and Micro-Agent Intelligence of ASI; likewise based on Einstein Equations of General Relativity, we make a T-Symmetry extension first, and then extend the 4-Dimensional Pseudo-Riemannian Manifold based Continuous Curved SpaceTime as part of MSpaceTime to N-Dimensional (1 ≪N< ∞) Pseudo-Riemannian Manifold based Continuous MSpaceTime extension, in modeling both Macro-Environment Intelligence and Macro-Agent Intelligence of ASI. Our discovery only solves the black box puzzle of AI, but also paves the way in achieving ASI through ADA. Of course, our Multiverse Endeavor will never stop from there.
Network Inference from Multi-omic Data Uncovers Dynamic Transcriptional Regulation Modules in Pathogenic Fungus Fusarium graminearum
Authors: Guo Li , Ji Mengjie , Ye Kai
Published: December 2019

The filamentous fungus Fusarium graminearum causes devastating crop disease and produces harmful mycotoxins worldwide. Understanding the complex F. graminearum transcriptional regulatory networks (TRNs) is vital for effective disease management. Reconstructing F. graminearum dynamic TRNs, an NP-hard problem, remains unsolved using commonly adopted reductionist or co-expression based approaches. Multi-omic data such as fungal genomic, transcriptomic data and phenomic data are vital to but so far have been largely isolated and untapped for unraveling phenotype-specific TRNs. Here for the first time, we harnessed these resources to infer global TRNs for F. graminearum using a Bayesian network based algorithm, “module networks”. The inferred TRNs contain 49 regulatory modules that show condition-specific gene regulation. Through a robust validation based on prior biological knowledge including functional annotations and TF binding site enrichment, our network prediction displayed high accuracy and concordance with existing knowledge, highlighted by its accurate capture of the well-known trichothecene gene cluster. In addition, we developed a new computational method to calculate the associations between modules and phenotypes, and discovered subnetworks responsible for fungal virulence, sexual reproduction and mycotoxin production. Finally, we found a clear compartmentalization of TRN modules in core and lineage-specific genomic regions in F. graminearum, reflecting the evolution of the TRNs in fungal speciation. This system-level reconstruction of filamentous fungal TRNs provides novel insights into the intricate networks of gene regulation that underlie key processes in F. graminearum pathobiology and offers promise for the development of improved disease control strategies.
Optogenetic control of Neisseria meningitidis Cas9 genome editing using an engineered, light-switchable anti-CRISPR protein
Authors: Hoffmann Mareike D. , Mathony Jan , Upmeier zu Belzen Julius , Harteveld Zander , Stengl Christina , Correia Bruno E. , Eils Roland , Niopek Dominik
Published: December 2019

Optogenetic control of CRISPR-Cas9 systems has significantly improved our ability to perform genome perturbations in living cells with high precision in time and space. As new Cas orthologues with advantageous properties are rapidly being discovered and engineered, the need for straightforward strategies to control their activity via exogenous stimuli persists. The Cas9 from Neisseria meningitidis (Nme) is a particularly small and target-specific Cas9 orthologue, and thus of high interest for in vivo genome editing applications.

Here, we report the first optogenetic tool to control NmeCas9 activity in mammalian cells via an engineered, light-dependent anti-CRISPR (Acr) protein. Building on our previous Acr engineering work, we created hybrids between the NmeCas9 inhibitor AcrIIC3 and the LOV2 blue light sensory domain from Avena sativa. Two AcrIIC3-LOV2 hybrids from our collection potently blocked NmeCas9 activity in the dark, while permitting robust genome editing at various endogenous loci upon blue light irradiation. Structural analysis revealed that, within these hybrids, the LOV2 domain is located in striking proximity to the Cas9 binding surface. Together, our work demonstrates optogenetic regulation of a type II-C CRISPR effector and might suggest a new route for the design of optogenetic Acrs.
Building a better biofilm - formation of in vivo-like biofilm structures by Pseudomonas aeruginosa in a porcine model of cystic fibrosis lung infection
Authors: Harrington Niamh E. , Sweeney Esther , Harrison Freya
Published: December 2019

Pseudomonas aeruginosa biofilm infections in the cystic fibrosis (CF) lung are highly resistant to current antimicrobial treatments and are associated with increased mortality rates. The existing models for such infections are not able to reliably mimic the clinical biofilms observed. We aimed to further optimise an ex vivo pig lung (EVPL) model for P. aeruginosa CF lung infection that can be used to increase understanding of chronic CF biofilm infection. The EVPL model will facilitate discovery of novel infection prevention methods and treatments, and enhanced exploration of biofilm architecture. We investigated purine metabolism and biofilm formation in the model using transposon insertion mutants in P. aeruginosa PA14 for key genes: purD, gacA and pelA. Our results demonstrate that EVPL recapitulates a key aspect of in vivo P. aeruginosa infection metabolism, and that the pathogen forms a biofilm with a clinically realistic structure not seen in other in vitro studies. Two pathways known to be required for in vivo biofilm infection - the Gac regulatory pathway and production of the Pel exopolysaccharide - are essential to the formation of this mature, structured biofilm on EVPL tissue. We propose the high-throughput EVPL model as a validated biofilm platform to bridge the gap between in vitro and CF lung infection.
The metronomic combination of paclitaxel with cholinergic agonists inhibits triple negative breast tumor progression. Participation of M2receptor subtype
Authors: Español Alejandro J. , Salem Agustina , Di Bari María , Cristofaro Ilaria , Sanchez Yamila , Tata Ada M. , Sales María E.
Published: December 2019

Triple negative tumors are more aggressive than other breast cancer subtypes and there is a lack of specific therapeutic targets on them. Since muscarinic receptors have been linked to tumor progression, we investigated the effect of metronomic therapy employing a traditional anti-cancer drug, paclitaxel plus muscarinic agonists at low doses on this type of tumor. We observed that MDA-MB231 tumor cells express muscarinic receptors, while they are absent in the non-tumorigenic MCF-10A cell line, which was used as control. The addition of carbachol or arecaidine propargyl ester, a non-selective or a selective subtype 2 muscarinic (M2) receptor agonist respectively, plus paclitaxel reduces cell viability involving a down-regulation in the expression of ATP “binding cassette” G2 drug transporter and epidermal growth factor receptor. We also detected an inhibition of tumor cell migration and anti-angiogenic effects produced by those drug combinationsin vitroandin vivo(in NUDE mice) respectively. Our findings provide substantial evidence about M2receptors as therapeutic target for the treatment of triple negative tumors.
Postnatal functional inactivation of the ventral subiculum enhances dopaminergic responses in the core part of the nucleus accumbens following ketamine injection in adult rats
Authors: Saoud Hana , De Beus Duco , Eybrard Séverine , Louilot Alain
Published: December 2019

For almost two decades schizophrenia has been considered to be a functional disconnection disorder. This functional disconnectivity between several brain regions could have a neurodevelopmental origin. Various approaches suggest the ventral subiculum (SUB) is a particular target region for neurodevelopemental disturbances in schizophrenia. It is also commonly acknowledged that there is a striatal dopaminergic (DA) dysregulation in schizophrenia which may depend on a subiculo-striatal disconnection involving glutamatergic NMDA receptors.

The present study was designed to investigate, in adult rats, the effects of the non-competitive NMDA receptor antagonist ketamine on DA responses in the ventral striatum, or, more specifically, the core part of the nucleus accumbens (Nacc), following postnatal functional inactivation of the SUB. Functional inactivation of the left SUB was carried out by local tetrodotoxin (TTX) microinjection at postnatal day 8 (PND8), i.e. at a critical point in the neurodevelopmental period. DA variations were recorded using in vivo voltammetry in freely moving adult rats (11 weeks). Locomotor activity was recorded simultaneously with the extracellular levels of DA in the core part of the Nacc. Data obtained during the present study showed that after administration of ketamine, the two indexes were higher in TTX animals than PBS animals, the suggestion being that animals microinjected with TTX in the left SUB at PND8 present greater reactivity to ketamine than animals microinjected with PBS. These findings could provide new information regarding the involvement of NMDA glutamatergic receptors in the core part of the Nacc in the pathophysiology of schizophrenia.
Intermittent access cocaine self-administration produces psychomotor sensitization: effects of withdrawal, sex and cross-sensitization
Authors: Carr Crystal C. , Ferrario Carrie R. , Robinson Terry E.
Published: December 2019

The psychomotor activating effects of drugs such as cocaine or amphetamine can change in very different ways – showing sensitization or tolerance – depending on whether they are administered more or less intermittently. This behavioral plasticity is thought to reflect, at least in part, changes in dopamine (DA) neurotransmission, and therefore, may provide insights into how repeated drug use promotes the development of substance use disorders. Indeed, the most widely used preclinical model of cocaine addiction, which involves Long Access (LgA) self-administration procedures, is reported to produce tolerance to cocaine’s psychomotor activating effects and effects on DA activity. This is cited as evidence in support of the view that in addiction, drug-seeking and-taking is motivated to overcome this DA deficiency and associated anhedonia. In contrast, Intermittent Access (IntA) cocaine self-administration is more effective than LgA in producing addiction-like behavior, but sensitizes DA neurotransmission. There is, however, very little information concerning the effects of IntA experience on the psychomotor activating effects of cocaine. The purpose of the studies reported here, therefore, was to determine whether IntA experience produces psychomotor sensitization with similar characteristics to that produced by the intermittent, noncontingent administration of cocaine. It did. The psychomotor sensitization produced by IntA experience with cocaine: (1) was greater after a long (30 days) vs short (1 day) period of withdrawal; (2) was greater in females than males; and (3) resulted in cross-sensitization to another psychomotor stimulant drug, amphetamine. This pattern of cocaine experience-dependent plasticity favors an incentive-sensitization view of addiction.
Revisiting the Global Workspace: Orchestration of the functional hierarchical organisation of the human brain
Authors: Deco Gustavo , Vidaurre Diego , Kringelbach Morten L.
Published: December 2019

A central, unsolved challenge in neuroscience is how the brain orchestrates function by organising the flow of information necessary for the underlying computation. It has been argued that this whole-brain orchestration is carried out by a core subset of integrative brain regions, commonly referred to as the ‘global workspace’, although quantifying the constitutive brain regions has proven elusive. We developed a normalised directed transfer entropy (NDTE) framework for determining the pairwise bidirectional causal flow between brain regions and applied it to multimodal whole-brain neuroimaging from over 1000 healthy participants. We established the full brain hierarchy and common regions in a ‘functional rich club’ (FRIC) coordinating the functional hierarchical organisation during rest and task. FRIC contains the core set of regions, which similar to a ‘club’ of functional hubs are characterized by a tendency to be more densely functionally connected among themselves than to the rest of brain regions from where they integrate information. The invariant global workspace is the intersection of FRICs across rest and seven tasks, and was found to consist of the precuneus, posterior and isthmus cingulate cortices, nucleus accumbens, putamen, hippocampus and amygdala that orchestrate the functional hierarchical organisation based on information from perceptual, long-term memory, evaluative and attentional systems. We confirmed the causal significance and robustness of this invariant global workspace by systematically lesioning a generative whole-brain model accurately simulating the functional hierarchy defined by NDTE. Overall, this is a major step forward in understanding the complex choreography of information flow within the functional hierarchical organisation of the human brain.
Artificial upward trends in Greek marine landings: a case of presentist bias in European fisheries
Authors: Tsikliras Athanassios C. , Dimarchopoulou Donna , Pardalou Androniki
Published: December 2019

According to the official landings as reported by the international databases for Greece, the declining trend of the Greek marine fisheries landings that had been continuous since the mid 1990s has been reversed during the last two years, with the total marine fisheries landings showing elevated catches after 2016. We claim that this upward trend is an artifact that is attributed to the combined reporting of the landings of additional fleets since 2016 that had been separately reported before and resulted in 20-30% inflation of the landings. In 2016, the Greek statistical authorities included the landings of 10 000 small-scale coastal vessels with engine horsepower lower than 20 HP together with the remaining coastal vessels, purse-seiners and trawlers whose landings formed the official reported Greek marine fisheries landings from 1970 to 2015. We acknowledge that this act of partial catch reconstruction improved the resolution of the landings and the officially reported values are now more realistic. However, the artificial, albeit inadvertent, inflation of the official Greek marine fisheries landings as they appear in international databases is a clear case of ‘presentist bias’ and may distort stock assessments and ecosystem modeling. As the currently misleading data stand, they are cause for substantial misinterpretation and analytical errors that can influence fisheries policy and have serious implications for fisheries management. We suggest that researchers should refrain from using the combined time-series and that a correction should be applied to the original time series (1970-2015) to account for the entire small-scale coastal fleet.
Trefoil factors share a lectin activity that defines their role in mucus
Authors: Järvå Michael , Lingford James P. , John Alan , Scott Nichollas E. , Goddard-Borger Ethan D.
Published: December 2019

The trefoil factors (TFFs) are disulfide-rich mucosal peptides that protect the epithelium by promoting cell migration and increasing the viscoelasticity of the mucosa. Here we show that all TFFs are divalent lectins that recognise the GlcNAc-α-1,4-Gal disaccharide, which terminates type-III mucin-like O-glycans. Structural, mutagenic and biophysical data support a model of mucus viscoelasticity that features non-covalent cross-linking of glycoproteins by TFFs.
Information content of cheek and lip colour in relation to the timing of ovulation in women
Authors: Rigaill Lucie
Published: December 2019

Various animal species have evolved a sexual communication system with females displaying and males discriminating information about the timing of ovulation through sexual signals. More research is now investigating the potential ovulatory signalling function of female red skin colour in human and non-human primates. However, to date it is still challenging to draft satisfying hypotheses about the evolution and function of female red skin colour, due to methodological discrepancies between human and non-human primate studies. The present study used a within-individual design and objective methods to analyse the relationship between fine-scale variation in cheek and lip colour (luminance and redness) and the estimated day of ovulation in 15 cycling women. Lip, but not cheek, colour appeared to contain information about the timing of ovulation, with lips getting darker around ovulation. This study adds to the growing evidence that female red skin colour may play a role in sexual signalling in human and non-human primates but also underlines variation in trait forms and functions at the species-level.
Phylogenomic analysis of the APETALA2 transcription factor subfamily across angiosperms reveals both deep conservation and lineage-specific patterns
Authors: Kerstens Merijn H.L. , Schranz M. Eric , Bouwmeester Klaas
Published: December 2019

The APETALA2 (AP2) subfamily of transcription factors are key regulators of angiosperm root, shoot, flower, and embryo development. The broad diversity of anatomical and morphological structures is potentially associated with the genomic dynamics of theAP2subfamily. However, a comprehensive phylogenomic analysis of theAP2subfamily across angiosperms is lacking. We combined phylogenetic and synteny analysis of distinctAP2subclades in the completed genomes of 107 angiosperm species. We identified major changes in copy number variation and genomic context within subclades across lineages, and discuss how these changes may have contributed to the evolution of lineage-specific traits. MultipleAP2subclades show highly conserved patterns of copy number and synteny across angiosperms, while others are more dynamic and show distinct lineage-specific patterns. As examples of lineage-specific morphological divergence due toAP2subclade dynamics, we hypothesize that that loss ofPLETHORA1/2in monocots correlates with the absence of taproots, whereas independent lineage-specific changes ofPLETHORA4/BABY BOOMandWRINKLED1genes in Brassicaceae and monocots point towards regulatory divergence of embryogenesis between these lineages. Additionally, copy number expansion ofTOE1andTOE3/AP2in asterids is implicated with differential regulation of flower development. Moreover, we show that the genomic context ofAP2s is in general highly specialised per angiosperm lineage. Our study is the first to shed light on the evolutionary divergence of theAP2subfamily subclades across major angiosperm lineages and emphasises the need for lineage-specific characterisation of developmental networks to further understand trait variability.

SIGNIFICANCE STATEMENT

APETALA2 transcription factors are crucial regulators of embryogenesis and post-embryonic development in plants. Characterising the genomic dynamics ofAPETALA2genes across 107 angiosperms provided evolutionary insights into gene-family and morphological divergence across major angiosperm lineages.
Paracrine and autocrine R-spondin signalling is essential for the maintenance and differentiation of renal stem cells
Authors: Vidal V.P.I. , Gregoire E. , Szenker-Ravi E. , Leushacke M. , Reversade B. , Chaboissier MC. , Schedl A.
Published: December 2019

During kidney development, WNT/β-catenin signalling has to be tightly controlled to ensure proliferation and differentiation of renal stem cells. Here we show that the two signalling molecules RSPO1 and RSPO3 act in a functionally redundant manner to permit WNT/β-catenin signalling and their genetic deletion leads to a rapid decline of renal progenitors. By contrast, tissue specific deletion in cap mesenchymal cells abolishes mesenchyme to epithelial transition (MET) that is linked to a loss ofBmp7expression, absence of SMAD1/5 phosphorylation and a concomitant failure to activateLef1, Fgf8andWnt4, thus explaining the observed phenotype on a molecular level. Surprisingly, the full knockout of LGR4/5/6, the cognate receptors of R-spondins, only mildly affects progenitor numbers, but does not interfere with MET. Taken together our data demonstrate key roles for R-spondins in permitting stem cell maintenance and differentiation and revealLgr-dependent and independent functions for these ligands during kidney formation.
The lysogenization of the non-O157Escherichia colistrains by stx-converting bacteriophage phi24B is associated with the O antigen loss and reduced fitness
Authors: Golomidova A.K. , Efimov A.D. , Kulikov E.E. , Kuznetsov A.S. , Letarov A.V.
Published: December 2019

The ability of the Shiga-toxigenicE. coli(STEC) to produce the toxin depends on the lysogenic conversion by stx-bacteriophages. The canonical stx-phage phi24B can lysogenize a wide variety ofE. colistrains.In vivothe secondary lysogenization of symbioticE. colistrains by the phages released by infecting STEC populations may contribute to the overall patient toxic load and to lead to the emergence of new pathogenic STEC strains. However, in our experiment all the phi24B lysogens obtained from the environmentalE. coliisolates had compromised O-antigen (Oag) biosynthesis. These lysogenic strains gained the sensitivity to the T5-like bacteriophages and featured increased sensitivity to the bactericidal activity of the horse serum. We conclude that in most ofE. colistrains the Oag effectively restricts phi24B infection. The lysogenic clones predominantly rise from the Oag deficient mutants and therefore they have reduced fitness compared to the parental strain.
MAtCHap: an ultra fast algorithm for solving the single individual haplotype assembly problem
Authors: Magi Alberto
Published: December 2019

Background

Human genomes are diploid, which means they have two homologous copies of each chromosome and the assignment of heterozygous variants to each chromosome copy, the haplotype assembly problem, is of fundamental importance for medical and population genetics.

While short reads from second generation sequencing platforms drastically limit haplotype reconstruction as the great majority of reads do not allow to link many variants together, novel long reads from third generation sequencing can span several variants along the genome allowing to infer much longer haplotype blocks.

However, the great majority of haplotype assembly algorithms, originally devised for short sequences, fail when they are applied to noisy long reads data, and although novel algorithm have been properly developed to deal with the properties of this new generation of sequences, these methods are capable to manage only datasets with limited coverages.

Results

To overcome the limits of currently available algorithms, I propose a novel formulation of the single individual haplotype assembly problem, based on maximum allele co-occurrence (MAC) and I develop an ultra-fast algorithm that is capable to reconstruct the haplotype structure of a diploid genome from low- and high-coverage long read datasets with high accuracy. I test my algorithm (MAtCHap) on synthetic and real PacBio and Nanopore human dataset and I compare its result with other eight state-of-the-art algorithms. All the results obtained by these analyses show that MAtCHap outperforms other methods in terms of accuracy, contiguity, completeness and computational speed.

Availability

MAtCHap is publicly available at https://sourceforge.net/projects/matchap/.
Developing synergistic drug combinations to restore antibiotic sensitivity in drug-resistant Mycobacterium tuberculosis
Authors: Omollo Charles , Singh Vinayak , Kigondu Elizabeth , Wasuna Antonina , Agarwal Pooja , Moosa Atica , Ioerger Thomas R. , Mizrahi Valerie , Chibale Kelly , Warner Digby F.
Published: December 2019

Tuberculosis (TB) is a leading global cause of mortality owing to an infectious agent, accounting for almost one-third of antimicrobial resistance (AMR) deaths annually. We aimed to identify synergistic anti-TB drug combinations with the capacity to restore therapeutic efficacy against drug-resistant mutants of the causative agent, Mycobacterium tuberculosis. We investigated combinations containing the known translational inhibitors, spectinomycin (SPT) and fusidic acid (FA), or the phenothiazine, chlorpromazine (CPZ), which disrupts mycobacterial energy metabolism. Potentiation of whole-cell drug efficacy was observed in SPT-CPZ combinations. This effect was lost against an M. tuberculosis mutant lacking the major facilitator superfamily (MFS) efflux pump, Rv1258c. Notably, the SPT-CPZ combination restored SPT efficacy against an SPT-resistant mutant carrying a g1379t point mutation in rrs, encoding the mycobacterial 16S ribosomal RNA. Combinations of SPT with FA, which targets the mycobacterial elongation factor G, exhibited potentiating activity against wild-type M. tuberculosis. Moreover, this combination produced a marginal potentiating effect against both FA-monoresistant and SPT-monoresistant mutants. Finally, combining SPT with the frontline anti-TB agents, rifampicin (RIF) and isoniazid, resulted in enhanced activity in vitro and ex vivo against both drug-susceptible M. tuberculosis and a RIF-monoresistant rpoB S531L mutant.These results support the utility of novel potentiating drug combinations in restoring antibiotic susceptibility of M. tuberculosis strains carrying genetic resistance to any one of the partner compounds.
Genomic investigation of the strawberry pathogen Phytophthora fragariae indicates pathogenicity is associated with transcriptional variation in three key races
Authors: Adams Thomas M. , Armitage Andrew D. , Sobczyk Maria K. , Bates Helen J. , Tabima Javier F. , Kronmiller Brent A. , Tyler Brett M. , Grünwald Niklaus J. , Dunwell Jim M. , Nellist Charlotte F. , Harrison Richard J.
Published: December 2019

The oomycete Phytophthora fragariae is a highly destructive pathogen of cultivated strawberry (Fragaria × ananassa), causing the root rotting disease, ‘red core’. The host-pathogen interaction has a well described gene-for-gene resistance relationship, but to date neither candidate avirulence nor resistance genes have been identified. We sequenced a set of American, Canadian and UK isolates of known race type, along with three representatives of the closely related pathogen of the raspberry (Rubus idaeus), Phytophthora rubi, and found a clear population structure, with a high degree of nucleotide divergence seen between some race types and abundant private variation associated with race types 4 and 5. In contrast, between isolates defined as UK races 1, 2 & 3 (UK1-2-3) there was no evidence of gene loss or gain; or the presence of insertions/deletions (INDELs) or Single Nucleotide Polymorphisms (SNPs) within or in proximity to putative pathogenicity genes could be found associated with race variation. Transcriptomic analysis of representative UK1-2-3 isolates revealed abundant expression variation in key effector family genes associated with pathogen race; however, further long read sequencing did not reveal any long range polymorphisms to be associated with avirulence to race UK2 or UK3 resistance, suggesting either control in trans or other stable forms of epigenetic modification modulating gene expression. This work reveals the combined power of population resequencing to uncover race structure in pathosystems and in planta transcriptomic analysis to identify candidate avirulence genes. This work has implications for the identification of putative avirulence genes in the absence of associated expression data and points towards the need for detailed molecular characterisation of mechanisms of effector regulation and silencing in oomycete plant pathogens.
Machine learning on drug-specific data to predict small molecule teratogenicity
Authors: Challa Anup P. , Beam Andrew L. , Shen Min , Peryea Tyler , Lavieri Robert R. , Lippmann Ethan S. , Aronoff David M.
Published: December 2019

Pregnant women are an especially vulnerable population, given the sensitivity of a developing fetus to chemical exposures. However, prescribing behavior for the gravid patient is guided on limited human data and conflicting cases of adverse outcomes due to the exclusion of pregnant populations from randomized, controlled trials. These factors increase risk for adverse drug outcomes and reduce quality of care for pregnant populations. Herein, we propose the application of artificial intelligence to systematically predict the teratogenicity of a prescriptible small molecule from information inherent to the drug. Using unsupervised and supervised machine learning, our model probes all small molecules with known structure and teratogenicity data published in research-amenable formats to identify patterns among structural, meta-structural, and in vitro bioactivity data for each drug and its teratogenicity score. With this workflow, we discovered three chemical functionalities that predispose a drug towards increased teratogenicity and two moieties with potentially protective effects. Our models predict three clinically-relevant classes of teratogenicity with AUC = 0.8 and nearly double the predictive accuracy of a blind control for the same task, suggesting successful modeling. We also present extensive barriers to translational research that restrict data-driven studies in pregnancy and therapeutically “orphan” pregnant populations. Collectively, this work represents a first-in-kind platform for the application of computing to study and predict teratogenicity.
TNFPred: Identifying tumor necrosis factors using hybrid features based on word embeddings
Authors: Nguyen Trinh-Trung-Duong , Le Nguyen-Quoc-Khanh , Ho Quang-Thai , Phan Dinh-Van , Ou Yu-Yen
Published: December 2019

Background

Cytokines are a class of small proteins that act as chemical messengers and play a significant role in essential cellular processes including immunity regulation, hematopoiesis, and inflammation. As one important family of cytokines, tumor necrosis factors have association with the regulation of a various biological processes such as proliferation and differentiation of cells, apoptosis, lipid metabolism, and coagulation. The implication of these cytokines can also be seen in various diseases such as insulin resistance, autoimmune diseases, and cancer. Considering the interdependence between this kind of cytokine and others, classifying tumor necrosis factors from other cytokines is a challenge for biological scientists. In this research, we employed a word embedding technique to create hybrid features which was proved to efficiently identify tumor necrosis factors given cytokine sequences. We segmented each protein sequence into protein words and created corresponding word embedding for each word. Then, word embedding-based vector for each sequence was created and input into machine learning classification models. When extracting feature sets, we not only diversified segmentation sizes of protein sequence but also conducted different combinations among split grams to find the best features which generated the optimal prediction. Furthermore, our methodology follows Chou’s 5-step rules to build a reliable classification tool.

Results

With our proposed hybrid features, prediction models obtain more promising performance compared to seven prominent sequenced-based feature kinds. Results from 10 independent runs on the surveyed dataset show that on an average, our optimal models obtain an area under the curve of 0.984 and 0.998 on 5-fold cross-validation and independent test, respectively.

Conclusions

These results show that biologists can use our model to identify tumor necrosis factors from other cytokines efficiently. Moreover, this study proves that natural language processing techniques can be applied reasonably to help biologists solve bioinformatics problems efficiently.
Liposomes Under Real Cell Conditions Behave Like Real Cells with a Single Pulsed Electric Field
Authors: Urabe Gen , Shimada Masaharu , Ogata Takumi , Katsuki Sunao
Published: December 2019

Liposomes are widely assumed to present a straightforward physical model of cells. However, almost all previous liposome experiments with pulsed electric fields (PEFs) have been conducted in low-conductivity liquids, a condition that differs significantly from that of cells in medium. Here, we prepared liposomes consisting of soy bean lecithin and cholesterol, at a molar ratio of 1:1, in higher-conductivity liquid that approximated the conditions of red blood cells in phosphate-buffered saline, with inner and outer liquid conductivities of 0.6 and 1.6 S/m, respectively. We found that a single 1.1 kV/cm, 400 μs PEF promoted cell-like spontaneous division of liposomes.
The endosomal protein sorting nexin 4 is a novel synaptic protein
Authors: Vazquez-Sanchez Sonia , Gonzalez-Lozano Miguel A. , Walfenzao Alexarae , Li Ka Wan , van Weering Jan R.T.
Published: December 2019

Sorting nexin 4 (SNX4) is an evolutionary conserved protein that mediates recycling from the endosomes back to the plasma membrane in yeast and mammalian cells. SNX4 is expressed in the brain, but its neuronal localization and function have not been addressed. Using a new antibody, endogenous neuronal SNX4 co-localized with both early and recycling endosomes, similar to the reported localization of SNX4 in non-neuronal cells. Neuronal SNX4 was accumulated in synapses, and immuno-electron microscopy revealed that SNX4 was predominantly localized to presynaptic terminals. Acute depletion of neuronal SNX4 using independent shRNAs did not affect the levels of the canonical SNX4-cargo transferrin receptor. Explorative mass spectrometry showed that each SNX4-targetted shRNA resulted in a reproducible and distinct proteome and that synaptic communication-related proteins were downregulated upon expression of the three shRNAs. The identification of SNX4 as a novel synaptic protein indicates a selective demand for SNX4 dependent sorting in synapses.