bluuebunny/crossref_metadata_2025_split huggingface dataset:
Occidiofungin, an actin binding antifungal within vivoefficacy in a vulvovaginal candidiasis infection
Authors: Ravichandran Akshaya , Geng Mengxin , Hull Kenneth G. , Romo Daniel , Lu Shi-En , Albee Aaron , Nutter Christopher , Gordon Donna M. , Ghannoum Mahmoud A. , Lockless Steve W. , Smith Leif 
Published: July 2018

AbstractCurrent antifungal treatment options are plagued with rapidly increasing occurrence of resistance, high degree of toxicity and a limited spectrum of activity. The need to develop a novel antifungal with a unique target, wider spectrum of activity, and reduced toxicity to the host, is urgent. We have identified and characterized one such compound named occidiofungin that is produced by the soil bacteriumBurkholderia contaminansMS14. This study identifies the primary cellular target of the antifungal, which was determined to be actin. Actin binding metabolites are generally characterized by their ability to inhibit polymerization or depolymerization of actin filaments, which presumably accounts for their severe toxicity. Occidiofungin, instead, has a subtler effect on actin dynamics that triggers apoptotic cell death. We were able to demonstrate the effectiveness of the antifungal in treating a vulvovaginal yeast infection in a murine model. This discovery puts occidiofungin in a unique class of actin-binding antifungal compounds with minimal reported toxicity to the host. The results of this study are important for the development of a novel class of antifungals that could fill the existing gap in treatment options for fungal infections.Author summaryWidespread resistance to antifungal compounds currently in use has been alarming. Identification and development of a new class of antifungals with a novel cellular target is desperately needed. This study describes the assays carried out to determine the molecular target and evaluate efficacy of one such novel antifungal compound called occidiofungin. Occidiofungin modified with a functional alkyne group enabled affinity purification assays and localization studies in yeast. These studies led to the identification of the actin binding property of occidiofungin. Actin-binding by secondary metabolites often exhibit severe host toxicity, but this does not appear to be the case for occidiofungin. We have previously been able to administer occidiofungin to mice at concentrations in the range of 5 mg/kg without any serious complications. We were able to demonstrate the effectiveness of the antifungal in treating a vaginal fungal infection in a murine model. The results outlined in this manuscript establish that occidiofungin is an efficacious compound with a novel molecular target, putting it in a completely new class of antifungals.
Myoglianin triggers the pre-metamorphosis stage in hemimetabolan insects
Authors: Kamsoi Orathai , Belles Xavier 
Published: July 2018

ABSTRACTInsect metamorphosis is triggered by a decrease in juvenile hormone (JH) in the final juvenile instar. What induces this decline is therefore a very relevant question. Working with the cockroachBlattella germanica, we found that Myoglianin (Myo), a ligand in the TGF-β signaling pathway, is highly expressed in the corpora allata (CA, the JH producing glands) and prothoracic glands (PG, which produce ecdysone) during the penultimate nymphal instar (N5). In the CA, high Myo levels during N5 repress the expression ofjhamt, a JH biosynthesis gene. In the PG, decreasing JH levels trigger gland degeneration, mediated by the factors Kr-h1, FTZ-F1, E93 and IAP1. Also in the PG, a peak ofmyoexpression in N5 stimulates the expression of ecdysone biosynthesis genes, such asnvd, thus enhancing the production of the metamorphic ecdysone pulse in N6. Themyoexpression peak in N5 also represses cell proliferation, which can contribute to enhance ecdysone production. The data indicate that Myo triggers the pre-metamorphic nymphal instar inB. germanica, and possibly in other hemimetabolan insects.
The Female Heart: Sex Differences in the Dynamics of ECG in Response to Stress
Authors: Adjei Tricia , Xue Jingwen , Mandic Danilo P. 
Published: July 2018

AbstractSex differences in the study of the human physiological response to mental stress are often erroneously ignored. To this end, we set out to show that our understanding of the stress response is fundamentally altered once sex differences are taken into account. This is achieved by comparing the heart rate variability (HRV) signals acquired during mental maths tests from ten females and ten males of similar maths ability; all females were in the follicular phase of their menstrual cycle. For rigour, the HRV signals from this pilot study were analysed using temporal, spectral and nonlinear signal processing techniques, which all revealed significant statistical differences between the sexes, with the stress-induced increases in the heart rates from the males being significantly larger than those from the females (p-value=2.2×10−3). In addition, mental stress produced an overall increase in the power of the low frequency component of HRV in the males, but caused an overall decrease in the females. The stress-induced changes in the power of the high frequency component were even more profound; it greatly decreased in the males, but increased in the females. We also show that mental stress was followed by the expected decrease in sample entropy, a nonlinear measure of signal regularity, computed from the males’ HRV signals, while overall, stress manifested in an increase in the sample entropy computed from the females’ HRV signals. This finding is significant, since mental stress is commonly understood to be manifested in the decreased entropy of HRV signals, however, the significant difference (p-value=2×10−9) in the changes in the entropies from the males and females highlights the pitfalls in ignoring sex in the formation of a physiological hypothesis. Furthermore, it has been argued that oestrogen attenuates the effect of catecholamine stress hormones; the findings from this investigation suggest for the first time that the conventionally cited cardiac changes, attributed to the fight-or-flight stress response, are not universally applicable to females. Instead, this pilot study provides an alternative interpretation of cardiac responses to stress in females, which indicates a closer alignment to the evolutionary tend-and-befriend response.
Exocyst subunit Sec6 is positioned by microtubule overlaps in the moss phragmoplast prior to the arrival of cell plate membrane
Authors: Tang Han , de Keijzer Jeroen , Overdijk Elysa , Sweep Els , Steentjes Maikel , Vermeer Joop E. , Janson Marcel E. , Ketelaar Tijs 
Published: July 2018

AbstractDuring plant cytokinesis a radially expanding membrane-enclosedcell plateis formed from fusing vesicles that compartmentalizes the cell in two. How fusion is spatially restricted to the site of cell plate formation is unknown. Aggregation of cell-plate membrane starts near regions of microtubule overlap within the bipolar phragmoplast apparatus of the mossPhyscomitrella patens. Since vesicle fusion generally requires coordination of vesicle tethering and subsequent fusion activity we analysed the subcellular localization of several subunits of the exocyst, a tethering complex active during plant cytokinesis. We found that Sec6, but neither Sec3 or Sec5 subunits localized to microtubule overlap regions in advance of cell plate construction started in moss. Moreover, Sec6 exhibited a conserved physical interaction with an orthologue of the Sec1/Munc18 protein KEULE, an important regulator for cell-plate membrane vesicle fusion in Arabidopsis. Recruitment of PpKEULE and vesicles to the early cell plate was delayed upon Sec6 gene silencing. Our findings thus suggest that vesicle-vesicle fusion is in part enabled by a pool of exocyst subunits at microtubule overlaps that is recruited independent of the delivery of vesicles.Summary statementWe performed a time-resolved localization screen of multiple subunits of the exocyst complex throughout moss cytokinesis and show that each subunit has a unique spatiotemporal recruitment pattern.
The Feeding Connectome: Convergence of Monosynaptic and Polysynaptic Sensory Paths onto Common Motor Outputs
Authors: Miroschnikow Anton , Schlegel Philipp , Schoofs Andreas , Hückesfeld Sebastian , Li Feng , Schneider-Mizell Casey M , Fetter Richard D , Truman James , Cardona Albert , Pankratz Michael J 
Published: July 2018

AbstractLittle is known about the organization of central circuits by which external and internal sensory inputs act on motor outputs to regulate fundamental behaviors such as feeding. We reconstructed, from a whole CNS EM volume, the synaptic map of input and output neurons that underlie food intake behavior ofDrosophilalarvae. The input neurons originate from enteric, pharyngeal and external sensory organs and converge onto seven distinct sensory synaptic compartments within the CNS, as defined by distribution patterns of their presynaptic sites. The output neurons consist of pharyngeal motor neurons, serotonergic modulatory neurons, and neuroendocrine neurons that target the ring gland, a key endocrine organ. Monosynaptic connections from a set of sensory synaptic compartments cover the motor and endocrine targets in overlapping domains. Polysynaptic routes can be superimposed on top of the monosynaptic connections, resulting in divergent sensory paths that converge on common motor outputs. A completely different set of sensory compartments is connected to the mushroom body calyx of the memory circuits. Our results illustrate a circuit architecture in which monosynaptic and multisynaptic connections from sensory inputs traverse onto output neurons via a series of converging paths.
Regional diversity in the postsynaptic proteome of the mouse brain
Authors: Roy Marcia , Sorokina Oksana , McLean Colin , Tapia-González Silvia , DeFelipe Javier , Armstrong J. Douglas , Grant Seth G. N. 
Published: July 2018

AbstractThe proteome of the postsynaptic terminal of excitatory synapses comprises over one thousand proteins in vertebrate species and plays a central role in behavior and brain disease. The brain is organized into anatomically distinct regions and whether the synapse proteome differs across these regions is poorly understood. Postsynaptic proteomes were isolated from seven forebrain and hindbrain regions in mice and their composition determined using proteomic mass spectrometry. Seventy-four percent of proteins showed differential expression and each region displayed a unique compositional signature. These signatures correlated with the anatomical divisions of the brain and their embryological origins. Biochemical pathways controlling plasticity and disease, protein interaction networks and individual proteins involved with cognition all showed differential regional expression. Combining proteomic and connectomic data shows that interconnected regions have specific proteome signatures. Diversity in synapse proteome composition is key feature of mouse and human brain structure.
Novel bir’s-foot trefoil RNA viruses provide insights into a clade of legume associated enamoviruses
Authors: Debat Humberto J. , Bejerman Nicolas 
Published: July 2018

AbstractBird’s-foot trefoil (Lotus corniculatus) is a nutritious forage crop, employed for livestock foraging around the world. Here, we report the identification and characterization of two novel viruses associated with bird’s-foot trefoil. Virus sequences with affinity to enamoviruses (ssRNA (+);Luteoviridae; Enamovirus) and nucleorhabdoviruses (ssRNA (-);Rhabdoviridae; Nucleorhabdovirus) were detected inL. corniculatustranscriptome data. The tentatively named birds-foot trefoil associated virus 1 (BFTV-1) genome organization is characterized by 13,626 nt long negative-sense ssRNA. BFTV-1 presents in its antigenome orientation six predicted gene products in the canonical order 3′-N-P-P3-M-G-L-5′. The proposed birds-foot trefoil associated virus 2 (BFTV-2) 5,736 nt virus sequence presents a typical 5′-PO-P1-2-IGS-P3-P5-3′ enamovirus genome structure. Phylogenetic analysis suggests that BFTV-1 is closely related toDatura yellow vein nucleorhabdovirus, and that BFTV-2 clusters into a monophyletic cluster of legumes-associated enamoviruses. This sub-clade of highly related and co-divergent legume associated viruses provides insights on the evolutionary history of the enamoviruses. The bioinformatic reanalysis of SRA libraries deposited in the NCBI database constitutes an emerging approach to the discovery of novel plant viruses which should be important for both quarantine purposes and disease management.
Distribution and asymptotic behavior of the phylogenetic transfer distance
Authors: Dávila Felipe Miraine , Entfellner Jean-Baka Domelevo , Lemoine Frédéric , Truszkowski Jakub , Gascuel Olivier 
Published: July 2018

AbstractThetransfer distance(TD) was introduced in the classification framework and studied in the context of phylogenetic tree matching. Recently, Lemoine et al. (2018) showed that TD can be a powerful tool to assess the branch support of phylogenies with large data sets, thus providing a relevant alternative to Felsenstein’s bootstrap. This distance allows areference branch βin a reference tree 𝒯 to be compared to a branchbfrom another treeT, both on the same set ofntaxa. The TD between these branches is the number of taxa that must be transferred from one side ofbto the other in order to obtainβ. By taking the minimum TD fromβto all branches inTwe define thetransfer index, denoted byϕ(β, T), measuring the degree of agreement ofβwithT. Let us consider a reference branchβhavingptips on its light side and define thetransfer support(TS) as 1 –ϕ(β, T)/(p –1). The aim of this article is to provide evidence thatp1 is a meaningful normalization constant in the definition of TS, and measure the statistical significance of TS, assuming thatβis compared to a tree T drawn according to a null model. We obtain several results that shed light on these questions in a number of settings. In particular, we study the asymptotic behavior of TS whenntends to ∞, and fully characterize the distribution ofϕwhenTis a caterpillar tree.
Computational fluid dynamic analysis reveals the underlying physical forces playing a role in 3D multiplex brain organoid cultures
Authors: Goto-Silva Livia , Ayad Nadia M. E. , Herzog Iasmin L. , Silva Nilton P. , Lamien Bernard , Orlande Helcio R. B. , Costa Souza Annie da , Ribeiro Sidarta , Martins Michele , Domont Gilberto B. , Junqueira Magno , Tovar-Moll Fernanda , Rehen Stevens K. 
Published: July 2018

AbstractOrganoid cultivation in suspension culture requires agitation at low shear stress to allow for nutrient diffusion, which preserves tissue structure. Multiplex systems for organoid cultivation have been proposed, but whether they meet similar shear stress parameters as the regularly used spinner flask and its correlation with the successful generation of brain organoids, has not been determined. Herein, we used computational fluid dynamics (CFD) analysis to compare two multiplex culture conditions: steering plates on an orbital shaker and the use of a previously described bioreactor. The bioreactor had low speed and high shear stress regions that may affect cell aggregate growth, depending on volume, whereas the CFD parameters of the steering plates were closest to the parameters of the spinning flask. Our protocol improves the initial steps of the standard brain organoid formation, and organoids produced therefrom displayed regionalized brain structures, including retinal pigmented cells. Overall, we conclude that suspension culture on orbital steering plates is a cost-effective practical alternative to previously described platforms for the cultivation of brain organoids for research and multiplex testing.HighlightsImprovements to organoid preparation protocolMultiplex suspension culture protocol successfully generate brain organoidsComputational fluid dynamics (CFD) reveals emerging properties of suspension culturesCFD of steering plates is equivalent to that of spinner flask cultures
Multi-scale analysis of schizophrenia risk loci: Integrating centenarian genomes and spatio-temporal expression profiles suggests the need for adjunctive therapeutic interventions for neuropsychiatric disorders
Authors: Anirudh Chellappa S , Pathak Ankit Kumar , Sinha Prashant , Jainarayanan Ashwin K. , Jain Sanjeev , Brahmachari Samir K. 
Published: July 2018

AbstractSchizophrenia (SZ) is a debilitating mental illness with multigenic etiology and significant heritability. Despite extensive genetic studies the molecular etiology has remained enigmatic. A recent systems biology study suggested a protein-protein interaction (PPI) network for SZ with 504 novel interactions. The onset of psychiatric disorders is predominantly during adolescence often accompanied by subtle structural abnormalities in multiple regions of the brain. The availability of BrainSpan atlas data allowed us to re-examine the genes present in SZ interactome as a function of space and time. The availability of genomes of healthy centenarians and non-psychiatric ExAC database allowed us to identify thevariants of criticality. The expression of SZ candidate genes responsible for cognition and disease onset were studied in different brain regions during particular developmental stages. A subset of novel interactors detected in the network was further validated using gene-expression data of post-mortem brains of patients with psychiatric illness. We have narrowed down the list of drug targets proposed by the previous interactome study to 10 proteins. These proteins belonging to 81 biological pathways, are targeted by 34 known FDA approved drugs that have distinct potential for treatment of neuropsychiatric disorders. We also report the possibility of targeting key genes belonging to Celecoxib pharmacodynamics, Gα signaling and cGMP-PKG signaling pathways, that are non-specific to schizophrenia etiology.
Estrogen-independent molecular actions of mutant estrogen receptor alpha in endometrial cancer
Authors: Blanchard Zannel , Vahrenkamp Jeffery M. , Berrett Kristofer C. , Arnesen Spencer , Gertz Jason 
Published: July 2018

AbstractEstrogen receptor 1 (ESR1) mutations have been identified in hormone therapy resistant breast cancer and primary endometrial cancer. Analyses in breast cancer suggests that mutant ESR1 exhibits estrogen independent activity. In endometrial cancer, ESR1 mutations are associated with worse outcomes and less obesity, however experimental investigation of these mutations has not been performed. Using a unique CRISPR/Cas9 strategy, we introduced the D538G mutation, a common endometrial cancer mutation that alters the ligand binding domain of ESR1, while epitope tagging the endogenous locus. We discovered estrogen-independent mutant ESR1 genomic binding that is significantly altered from wildtype ESR1. The D538G mutation impacted expression, including a large set of non-estrogen regulated genes, and chromatin accessibility, with most affected loci bound by mutant ESR1. Mutant ESR1 is unique from constitutive ESR1 activity as mutant-specific changes are not recapitulated with prolonged estrogen exposure. Overall, D538G mutant ESR1 confers estrogen-independent activity while causing additional regulatory changes in endometrial cancer cells that are distinct from breast cancer cells.
Male and female mice demonstrate divergent cellular responses in the bed nucleus of stria terminalis (BNST) following morphine withdrawal
Authors: Luster Brennon R. , Cogan Elizabeth S. , Schmidt Karl T. , Pati Dipanwita , Pina Melanie M. , Dange Kedar , McElligott Zoé A. 
Published: July 2018

AbstractThe United States is experiencing an opioid epidemic of significant proportions, imposing enormous fiscal and societal costs. While prescription opioid analgesics are essential for treating pain, the cessation of these drugs can induce a withdrawal syndrome, and thus opioid use often persists to alleviate or avoid these symptoms. Therefore, it is essential to understand the neurobiology underlying this critical window of withdrawal from opioid analgesics to prevent continued usage. To model this, we administered a low dose of morphine, and precipitated withdrawal with naloxone to investigate the behavioral and cellular responses in C57BL/6J male and female mice. Following 3 days of administration, both male and female mice sensitized to the repeated bouts of withdrawal, as evidenced by their composite global withdrawal score. Female mice exhibited increased withdrawal symptoms on some individual measures, but did not show characteristic weight loss observed in male mice. Because of its role in mediating withdrawal-associated behaviors, we examined neuronal excitability and inhibitory synaptic transmission in the bed nucleus of the stria terminalis (BNST) 24 hours following the final precipitated withdrawal. In male mice, morphine withdrawal increased spontaneous GABAergic signaling compared to controls. In contrast, morphine withdrawal decreased spontaneous GABAergic signaling, and increased BNST projection neuron excitability in female mice. Intriguingly, these opposing GABAergic effects were dependent on within slice excitability. Our findings suggest that male and female mice manifest divergent cellular responses in the BNST following morphine withdrawal, and alterations in BNST inhibitory signaling may be a significant factor contributing to the expression of behaviors following opioid withdrawal.
A novel virtual plus-maze for studying electrophysiological correlates of spatial reorientation
Authors: Török Ágoston , Kóbor Andrea , Honbolygó Ferenc , Baker Travis 
Published: July 2018

AbstractQuick reorientation is an essential part of successful navigation. Despite growing attention to this ability, little is known about how reorientation happens in humans. To this aim, we recorded EEG from 34 participants. Participants were navigating a simple virtual reality plus-maze where at the beginning of each trial they were randomly teleported to either the North or the South alley. Results show that the teleportation event caused a quick reorientation effect over occipito-parietal areas as early as 100 msec; meaning that despite the known stochastic nature of the teleportation, participants built up expectations for their place of arrival. This result has important consequences for the optimal design of Virtual reality locomotion.
transcranial Direct Current Stimulation Studies Open Database (tDCS-OD)
Authors: Grossman Pnina , Alekseichuk Ivan , de Lara Gabriel , Paneri Kunal , Kunz Patrik , Turi Zsolt , Bikson Marom , Paulus Walter , Antal Andrea 
Published: July 2018

AbstractTranscranial direct current stimulation (tDCS) is increasingly evaluated for a myriad of clinical indications and performance enhancement mainly related to cognitive and motor applications. As a result tDCS has been tested with diverse inclusion criteria and subject populations. tDCS is customized for applications by many factors, including stimulation dose (montage, current, time), associated training and subject inclusion/exclusion criteria. The rapid proliferation of applications, technological advancements and emerging scientific discoveries presents challenges to the organization and consolidation of tDCS data – which can lead to scientific, clinical and public confusions. In this paper, we develop a system to summarize and consolidate methodological aspects of tDCS, concentrating on study design and the physical parameters of the stimulation. We introduce a community-driven, open access database, where these parameters, including stimulation intensities, duration, electrode sizes, montages, and subject information, are noted for relevant tDCS publications. The transcranial Direct Current Stimulation Studies Open Database (tDCS-OD) (http://tdcsdatabase.com) will support constructive dialogue on research and clinical tDCS applications, critical evaluation of past work, and identification of promising protocols, while reducing ambiguity about stimulation methodology. The database design allows ongoing updates and editing, with transparent version control. At the moment, the database includes information about 56,613 tDCS sessions.