bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phage-Antibiotic Synergy is Driven by a Unique Combination of Antibacterial Mechanism of Action and Stoichiometry
Authors: Liu Carmen Gu , Green Sabrina I. , Min Lorna , Clark Justin R. , Salazar Keiko C. , Terwilliger Austen L. , Kaplan Heidi B. , Trautner Barbara W. , Ramig Robert F. , Maresso Anthony W. 
Published: February 2020

AbstractThe continued rise in antibiotic resistance is precipitating a medical crisis. Bacteriophage (phage) has been hailed as one possible therapeutic option to augment the efficacy of antibiotics. However, only a handful of studies have addressed the synergistic relationship between phage and antibiotics. Here, we report a comprehensive analysis of phage-antibiotic interaction that evaluates synergism, additivism, and antagonism for all classes of antibiotics across clinically achievable stoichiometries. We combined an optically-based real-time microtiter plate readout with a matrix-like heatmap of treatment potencies to measure phage and antibiotic synergy (PAS), a process we term synography. Phage-antibiotic synography was performed against a pandemic drug-resistant clonal group ofE. coli(ExPEC) with antibiotic levels blanketing the minimum inhibitor concentration (MIC) across seven orders of viral titers. Our results suggest that, under certain conditions, phages provide an adjuvating effect by lowering the MIC for drug-resistant strains. Furthermore, synergistic and antagonistic interactions are highly dependent on the mechanism of bacterial inhibition by the class of antibiotic paired to the phage, and when synergism is observed, it suppresses the emergence of resistant cells. Host conditions that simulate the infection environment, including serum and urine, suppress PAS in a bacterial growth-dependent manner. Lastly, phage burst size seems to be a significant driver of synergism. Collectively, this data suggests lytic phages can resuscitate an ineffective antibiotic for previously resistant bacteria, while also synergize with antibiotics in a class-dependent manner, processes that may be dampened by lower bacterial growth rates found in host environments.Significance StatementBacteriophage (phage) therapy is a promising approach to combat the rise of multi-drug resistant bacteria. Currently, the preferred clinical modality is to pair phage with an antibiotic, a practice thought to improve efficacy. However, antagonism between phage and antibiotics has been reported, the choice of phage and antibiotic is not often empirically determined, and the effect of the host factors on the effectiveness is unknown. Here, we interrogate phage-antibiotic interactions across antibiotics with different mechanisms of action. Our results suggest that phage can lower the working MIC for bacterial strains already resistant to the antibiotic, is dependent on the antibiotic class and stoichiometry of the pairing, and is dramatically influenced by the host microenvironment.
Artificial diets modulate infection rates byNosema ceranaein bumblebees
Authors: Gómez-Moracho Tamara , Durand Tristan , Pasquaretta Cristian , Heeb Philipp , Lihoreau Mathieu 
Published: February 2020

AbstractParasites alter the physiology and behaviour of their hosts. In domestic honey bees, the microsporidiaNosema ceranaeinduces an energetic stress and impairs the behaviour of foragers, potentially leading to colony collapse. Whether this emerging parasite similarly affects wild pollinators is little understood because of the low success rates of experimental infection protocols. Here we established a new apporach for infecting bumblebees (Bombus terrestris) with controlled amounts ofN. ceranae, by briefly exposing individual bumblebees to a sucrose solution containing parasite spores, before feeding them with artificial diets. We validated our protocol by testing the effect of two spore dosages and two diets varying in their protein to carbohydrate ratio, on the prevalence of the parasite (proportion of infected bees), the intensity of infection (spore count in the gut), and the survival of bumblebees. Insects fed a low-protein high-carbohydrate diet showed highest parasite prevalence (up to 70%) but lived longest, suggesting that immunity and survival of bumblebees are maximised at different protein to carbohydrate ratios. Spore dosage had no effect on parasite infection rate and host survival. The identification of experimental conditions for successfully infecting bumblebees withN. ceranaein the lab will facilitate investigations of the sub-lethal effects of this parasite on the behaviour and cognition of wild pollinators.
CandiHap: a toolkit for haplotype analysis for sequence of samples and fast identification of candidate causal gene(s) in genome-wide association study
Authors: Li Xukai , Shi Zhiyong , Qie Qianru , Gao Jianhua , Wang Xingchun , Han Yuanhuai 
Published: February 2020

AbstractGenome-wide association study (GWAS) is widely used to identify genes involved in plants, animals and human complex traits. Generally, the identified SNP is not necessarily the causal variant, but it is rather in linkage disequilibrium (LD). One key challenge for GWAS results interpretation is to rapidly identify causal genes and provide profound evidence on how they affect the trait. Researches want to identify candidate causal variants from the most significant SNPs of GWAS in any species and on their local computer, while to complete these tasks are to be time-consuming, laborious and prone to errors and omission. To our knowledge, so far there is no tool available to solve the challenge for GWAS data very quickly. Based on the standard VCF (variant call format) format, CandiHap is developed to fast preselection candidate causal SNPs and gene(s) from GWAS by integrating LD result, SNP annotation, haplotype analysis and traits statistics of haplotypes. Investigators can specify genes or linkage regions based on GWAS results, linkage disequilibrium (LD), and predicted candidate causal gene(s). It supported Windows, Mac and Linux computers and servers in graphical interface and command line, and applied to any other plant, animal or bacteria species. The source code of CandiHap tool is freely available athttps://github.com/xukaili/CandiHap
Colonization with the commensal fungusCandida albicansperturbs the gut-brain axis through dysregulation of endocannabinoid signaling
Authors: Markey Laura , Hooper Andrew , Melon Laverne C. , Baglot Samantha , Hill Matthew N. , Maguire Jamie , Kumamoto Carol A. 
Published: February 2020

AbstractAnxiety disorders are the most prevalent mental health disorder worldwide, with a lifetime prevalence of 5-7% of the human population. Although the etiology of anxiety disorders is incompletely understood, one aspect of host health that affects anxiety disorders is the gut-brain axis. We used a mouse model of gastrointestinal (GI) colonization to demonstrate that the commensal fungusCandida albicansaffects host health via the gut-brain axis. In mice, bacterial members of the gut microbiota can influence the host gut-brain axis, affecting anxiety-like behavior and the hypothalamus-pituitary-adrenal (HPA) axis which produces the stress hormone corticosterone (CORT). Here we showed that mice colonized withC. albicansdemonstrated increased anxiety-like behavior and increased basal production of CORT as well as dysregulation of CORT production following acute stress. The HPA axis and anxiety-like behavior are negatively regulated by the endocannabinoid anandamide (AEA).C. albicans-colonizedmice exhibited systemic changes in the endocannabinoidome, within the GI tract and the brain, and showed a negative correlation between brain AEA levels and serum CORT. Further, increasing AEA levels using the well-characterized fatty acid amide hydrolase (FAAH) inhibitor URB597 was sufficient to reverse both neuroendocrine phenotypes inC. albicans-colonizedmice. Thus, a commensal fungus that is a common colonizer of humans had widespread effects on the physiology of its host. To our knowledge, this is the first report of microbial manipulation of the endocannabinoid (eCB) system that resulted in neuroendocrine changes contributing to anxiety-like behavior.
The serine-threonine kinase TAO3 promotes cancer invasion and tumor growth by facilitating trafficking of endosomes containing the invadopodia scaffold TKS5α
Authors: Iizuka Shinji , Quintavalle Manuela , Navarro Jose Ceja , Gribbin Kyle P. , Ardecky Robert J. , Abelman Matthew , Ma Chen-Ting , Sergienko Eduard , Zeng Fu-Yue , Pass Ian , Thomas George , McWeeney Shannon , Hassig Christian A. , Pinkerton Anthony B , Courtneidge Sara A 
Published: February 2020

ABSTRACTInvadopodia are actin-based proteolytic membrane protrusions required for invasive behavior and tumor growth. We used our high-content screening assay to identify kinases impacting invadopodia formation. Among the top hits we selected TAO3, a STE20-like kinase of the GCK subfamily, for further analysis. TAO3 was over-expressed in many human cancers, and regulated invadopodia formation in melanoma, breast and bladder cancers. Furthermore, TAO3 catalytic activity facilitated melanoma growth in 3-dimensional matrices andin vivo. We developed potent catalytic inhibitors of TAO3 that inhibited invadopodia formation and function, and tumor cell extravasation and growth. Using these inhibitors, we determined that TAO3 activity was required for endosomal trafficking of TKS5α, an obligate invadopodia scaffold protein. A phosphoproteomics screen for TAO3 substrates revealed the dynein subunit protein LIC2 as a relevant substrate. Knockdown of LIC2 or expression of a phosphomimetic form promoted invadopodia formation. Thus, TAO3 is a new therapeutic target with a distinct mechanism of action.SIGNIFICANCETargeting tumor invasive behavior represents an understudied opportunity. We used an unbiased screening approach to identify kinases required for invadopodia formation and function. We validated TAO3, both genetically and with a novel inhibitor, and determined TAO3 function. Our data support clinical development of this class of target.
Seizure onset location shapes dynamics of initiation
Authors: Salami Pariya , Peled Noam , Nadalin Jessica K. , Martinet Louis-Emmanuel , Kramer Mark A. , Lee Jong W. , Cash Sydney S. 
Published: February 2020

AbstractObjectiveIctal electrographic patterns are widely thought to reflect underlying neural mechanisms of seizures. Here we studied the degree to which seizure patterns are consistent in a given patient, relate to particular brain regions and if two candidate biomarkers (high-frequency oscillations, HFOs; infraslow activity, ISA) and network activity, as assessed with cross-frequency interactions, can discriminate between seizure types.MethodsWe analyzed temporal changes in low and high frequency oscillations recorded during seizures, as well as phase-amplitude coupling (PAC) to monitor the interactions between delta/theta and ripple/fast ripple frequency bands at seizure onset.ResultsSeizures of multiple pattern types were observed in a given patient and brain region. While there was an increase in HFO rate across different electrographic patterns, there are specific relationships between types of HFO activity and onset region. Similarly, changes in PAC dynamics were more closely related to seizure onset region than they were to electrographic patterns while ISA was a poor indicator for seizure onset.ConclusionsOur findings suggest that the onset region sculpts neurodynamics at seizure initiation and that unique features of the cytoarchitecture and/or connectivity of that region play a significant role in determining seizure mechanism.SignificanceClinicians should consider more than just overt electrographic patterns when considering seizure mechanisms and regions of onset. Examination of onset pattern in conjunction with the interactions between different oscillatory frequencies in the context of different brain regions might be more informative and lead to more reliable clinical inference as well as novel therapeutic approaches.
Phylogenomic analysis ofClostridiodes difficileribotype 106 strains reveals novel genetic islands and emergent phenotypes
Authors: Roxas Bryan Angelo P. , Roxas Jennifer Lising , Claus-Walker Rachel , Harishankar Anusha , Mansoor Asad , Anwar Farhan , Jillella Shobitha , Williams Alison , Lindsey Jason , Elliott Sean P. , Shehab Kareem W. , Viswanathan V.K. , Vedantam Gayatri 
Published: February 2020

ABSTRACTBackgroundClostridioides difficileRT106 has emerged as a dominant molecular type in the USA in recent years, but the underlying factors contributing to its predominance remain undefined. As part of our ongoingC. difficileinfection (CDI) surveillance in Arizona, we monitored RT106 frequency and characterized the genomic and phenotypic properties of the recovered isolates.ResultsFrom 2015-2018, RT106 was the second-most prevalent molecular type isolated from CDI patients in our surveillance. A representative RT106 strain displayed robust virulence and 100% lethality in the hamster model of acute CDI. We identified a unique 46 KB genomic island (GI1) in all RT106 strains, including those in public databases. GI1 was not found in its entirety in any otherC. difficileclade, or indeed in any other microbial genome; however, smaller segments were detected in selectEnterococcus faeciumstrains. Molecular clock analyses suggest that GI1 was horizontally acquired and sequentially assembled over time. Consistent with the presence of genes encoding homologs of VanZ and a SrtB-anchored collagen-binding adhesin in GI1, all tested RT106 strains had increased teicoplanin resistance and a majority displayed collagen-dependent biofilm formation. Two additional genomic islands (GI2 and GI3) were also present in a subset of RT106 strains. All three islands have features of mobile genetic elements and encode several putative virulence factors.ConclusionsConsistent with the known genetic plasticity ofC. difficile, strains belonging to the RT106 clade harbor unique genetic islands. Correspondingly, emergent phenotypic properties may contribute to the relatively rapid shifts of strain distribution in patient populations.
Deficits in olfactory sensitivity in a mouse model of Parkinson’s disease revealed by plethysmography of odor-evoked sniffing
Authors: Johnson Michaela E. , Bergkvist Liza , Mercado Gabriela , Stetzik Lucas , Meyerdirk Lindsay , Brundin Patrik , Wesson Daniel W. 
Published: February 2020

AbstractHyposmia is evident in over 90% of Parkinson’s disease (PD) patients. A characteristic of PD is intraneuronal deposits composed in part of α-synuclein fibrils. Based on the analysis of post-mortem PD patients, Braak and colleagues suggested that early in the disease α-synuclein pathology is present in the dorsal motor nucleus of the vagus, as well as the olfactory bulb and the anterior olfactory nucleus, and then later affects other interconnected brain regions. Here, we bilaterally injected α-synuclein preformed fibrils into the olfactory bulb of wild type male and female mice. Six-months after injection, the anterior olfactory nucleus and the piriform cortex displayed a high α-synuclein pathology load. We evaluated olfactory perceptual function by monitoring odor-evoked sniffing behavior in a plethysmograph at one-, three- and six-months after injection of α-synuclein fibrils. At all-time points, females injected with fibrils exhibited reduced odor detection sensitivity, which was detectable with the semi-automated plethysmography apparatus, but not a buried pellet test. In future studies, this sensitive methodology we used to assess olfactory detection deficits could be used to define how α-synuclein pathology affects other aspects of olfactory perception in PD models and to clarify the neuropathological underpinnings of these deficits.Highlights- α-synuclein pathology spreads through neuronally-connected areas after bilateral injection of preformed fibrils into the olfactory bulb.- A plethysmograph and an olfactometer were used for a semi-automated screen of odor-evoked sniffing as an assay for odor detection sensitivity.- Bilateral olfactory bulb injections of α-synuclein preformed fibrils in female mice led to reduced sensitivity for detecting odors.- The semi-automated plethysmography apparatus was more sensitive at detecting odor detection deficits than the buried pellet test.
On the effects of climate change on Galápagos green turtleChelonia mydas agassiziineonate mortality in A1B
Authors: Gotts Max 
Published: February 2020

AbstractClimate change affects every crevice and corner of the ecological world. Already we see seasonal effects on important ecosystems such as the marine habitats of the Galápagos Archipelago. This paper looks at the year 2100 in the IPCC scenario A1B, looking specifically atChelonia mydas agassiziiand seeing whether it will be a “winner” or a “loser” under climate change. We discover that while neonate hatchlings may benefit from a compressed laying period that offers them protection by way of numbers, and speed from the increased ocean temperatures (SST), they lose out many other places. Frigatebird and reef fish predation will increase, hatchling size and fitness may decrease, and a surplus of female hatchlings will be produced, or none at all as nest temperatures rise above the thermal mortality limit.Chelonia mydas agassiziiwill need serious conservation help if we wish to keep it on this earth by the year 2100 even if we opt for the A1B strategy.
Quantification of Adeno-Associated Virus with Safe Nucleic Acid Dyes
Authors: Xu Jian , DeVries Steven H , Zhu Yongling 
Published: February 2020

AbstractAdeno-associated virus (AAV) is the most commonly used viral vector for both biological and gene therapeutic applications1. Although many methods have been developed to measure quantity attributes of AAV, they are often technically challenging and time consuming. Here we report a method to titer AAV with GelGreen® dye, a safe green fluorescence nucleic acid dye recently engineered by Biotium company (Fremont, CA). This method, hereinafter referred to as GelGreen method, provides a fast (~ 30 minutes) and reliable strategy for AAV titration. To validate GelGreen method, we measured genome titer of an AAV reference material AAV8RSM and compared our titration results with those determined by Reference Material Working Group (ARMWG). We showed that GelGreen results and capsid Elisa results are comparable to each other. We also showed that GelRed® dye, a red fluorescence dye from Biotium, can be used to directly “visualize” AAV genome titer on a conventional gel imager, presenting an especially direct approach to estimate viral quantity. In summary, we described a technique to titer AAV by using new generation of safe DNA dyes. This technique is simple, safe, reliable and cost-efficient. It has potential to be broadly applied for quantifying and normalizing AAV viral vectors.
Evolution of genome structure in theDrosophila simulansspecies complex
Authors: Chakraborty Mahul , Chang Ching-Ho , Khost Danielle E. , Vedanayagam Jeffrey , Adrion Jeffrey R. , Liao Yi , Montooth Kristi L. , Meiklejohn Colin D. , Larracuente Amanda M. , Emerson J.J. 
Published: February 2020

ABSTRACTThe rapid evolution of repetitive DNA sequences, including satellite DNA, tandem duplications, and transposable elements, underlies phenotypic evolution and contributes to hybrid incompatibilities between species. However, repetitive genomic regions are fragmented and misassembled in most contemporary genome assemblies. We generated highly contiguousde novoreference genomes for theDrosophila simulansspecies complex (D. simulans, D. mauritiana, andD. sechellia), which speciated ∼250,000 years ago. Our assemblies are comparable in contiguity and accuracy to the currentD. melanogastergenome, allowing us to directly compare repetitive sequences between these four species. We find that at least 15% of theD. simulanscomplex species genomes fail to align uniquely toD. melanogasterdue to structural divergence—twice the number of single-nucleotide substitutions. We also find rapid turnover of satellite DNA and extensive structural divergence in heterochromatic regions, while the euchromatic gene content is mostly conserved. Despite the overall preservation of gene synteny, euchromatin in each species has been shaped by clade and species-specific inversions, transposable elements, expansions and contractions of satellite and tRNA tandem arrays, and gene duplications. We also find rapid divergence among Y-linked genes, including copy number variation and recent gene duplications from autosomes. Our assemblies provide a valuable resource for studying genome evolution and its consequences for phenotypic evolution in these genetic model species.
Fast, Rate-Independent, Finite Element Implementation of a 3D Constrained Mixture Model of Soft Tissue Growth and Remodeling
Authors: Latorre Marcos , Humphrey Jay D. 
Published: February 2020

AbstractConstrained mixture models of soft tissue growth and remodeling can simulate many evolving conditions in health as well as in disease and its treatment, but they can be computationally expensive. In this paper, we derive a new fast, robust finite element implementation based on a concept of mechanobiological equilibrium that yields fully resolved solutions and allows computation of quasi-equilibrated evolutions when imposed perturbations are slow relative to the adaptive process. We demonstrate quadratic convergence and verify the model via comparisons with semi-analytical solutions for arterial mechanics. We further examine the enlargement of aortic aneurysms for which we identify new mechanobiological insights into factors that affect the nearby non-aneurysmal segment as it responds to the changing mechanics within the diseased segment. Because this new 3D approach can be implemented within many existing finite element solvers, constrained mixture models of growth and remodeling can now be used more widely.
Brassinosteroids Suppress Ethylene Biosynthesis via Transcription Factor BZR1 in Pear and Apple Fruit
Authors: Ji Yinglin , Qu Yi , Jiang Zhongyu , Su Xin , Yue Pengtao , Li Xinyue , Wang Yanan , Bu Haidong , Yuan Hui , Wang Aide 
Published: February 2020

ABSTRACTThe plant hormone ethylene is important for the ripening of climacteric fruit, such as pear (Pyrus ussuriensis), and the brassinosteroid (BR) class of phytohormones affects ethylene biosynthesis during ripening, although via an unknown molecular mechanism. Here, we observed that exogenous BR treatment suppressed ethylene production during pear fruit ripening, and that the expression of the transcription factorPuBZR1was enhanced by epibrassinolide (EBR) treatment during pear fruit ripening. PuBZR1 was shown to interact with PuACO1, which converts 1-aminocyclopropane-1-carboxylic acid (ACC) to ethylene, and suppress its activity. We also observed that BR-activated PuBZR1 bound to the promoters ofPuACO1and ofPuACS1a, which encodes ACC synthase, and directly suppressed their transcription. Moreover, PuBZR1 suppressed the expression of transcription factorPuERF2by binding its promoter, and PuERF2 bound to the promoters ofPuACO1andPuACS1a. We concluded that PuBZR1 indirectly suppresses the transcription ofPuACO1andPuACS1athrough its regulation of PuERF2. Ethylene production and the expression profiles of the corresponding apple (Malus domestica) homologs showed similar changes following EBR treatment. Together, these results suggest that BR-activated BZR1 suppresses ACO1 activity and the expression ofACO1andACS1a, thereby reducing ethylene production during pear and apple fruit ripening. This likely represents a conserved mechanism by which exogenous BR suppresses ethylene biosynthesis during climacteric fruit ripening.One-sentence summaryBR-activated BZR1 suppresses ACO1 activity and expression ofACO1andACS1a, which encode two ethylene biosynthesis enzymes, thereby reducing ethylene production during pear and apple fruit ripening.