bluuebunny/crossref_metadata_2025_split huggingface dataset:
In VitroPotent Activity of ε-poly-L-lysine againstCandida albicansand the Underlying Mechanisms
Authors: Wei Lian-hua , Yu Tian , Wang Xiao-ning , Hou Jin-xia , Wang Xin , Wang Chuan , Li Ke-ke , Jing Shuang-yan , Zhang Xu 
Published: April 2019

AbstractObjectiveThis study aimed to examine the antifungal activity of ε-poly-L-lysine (ε-PL) against the planktonic cells or biofilms ofCandida albicansand explore the underlying mechanism.MethodsThe minimal inhibitory concentration, minimum fungal concentration, and sessile minimal inhibitory concentration were estimated. The germ tube formation and yeast-to-hypha transformation ofC. albicansin different media that induced mycelial growth were recorded. The effect of different concentrations of ε-PL on the biofilm formation process and mature biofilm ofC. albicanswas determined. The reactive oxygen species (ROS) and malondialdehyde (MDA) contents ofC. albicansafter ε-PL treatment were measured. The changes in major virulence genes and proteins ofC. albicanswere detected.Resultsε-PL (512 μg/mL) exerted a strong inhibitory effect onC. albicansand biofilms. It blocked the yeast-to-hypha transition and reduced the germ tube formation and germ tube length ofC. albicans. The MDA and ROS contents showed an upward trend, indicating a positive correlation with the concentration. Further, ε-PL inhibited the high expression of virulence genes in oxidative stress induced byC. albicans. The main peak in the mass spectrum ofC. albicanswas found to be clear.Conclusionsε-PL exerted a significant antifungal effect on the phytoplankton and biofilm ofC. albicans. High concentrations of ε-PL significantly inhibited the main mycelium ofC. albicans. ε-PL induced ROS, released cytochrome C, attacked theC. albicanscell membrane to aggravate its lipid oxidation, and inhibited the expression ofC. albicans–associated virulence genes and proteins, thereby exerting a bacteriostatic effect.ImportanceThe last two decades have seen a growing trend toward the failure of current antifungal drugs attributed toCandidabiofilms. Under appropriate conditions, adherence and colonization of planktonic cells on host tissues and medical devices initiate multicellular organization called biofilm, which is an organized heterogeneous mixture of yeast, hyphae, and pseudohyphal forms embedded in a complex extracellular matrix. Compared with the planktonic cells, biofilms show high resistance to a wide variety of antifungal agents and tolerance to harsh environments and host immune system. Moreover, the development of antifungal drugs is costly, long-term, and difficult. Thus, researchers turned their attention to natural antibacterial peptides, hoping to find an effective antifungal substance or enhance the sensitivity of the existing antifungal drugs toC. albicans.
Structure and autoregulation of a P4-ATPase lipid flippase
Authors: Timcenko Milena , Lyons Joseph A. , Januliene Dovile , Ulstrup Jakob , Dieudonne Thibaud , Montigny Cedric , Ash Miriam Rose , Karlsen Jesper Lykkegaard , Boesen Thomas , Kühlbrandt Werner , Lenoir Guillaume , Möller Arne , Nissen Poul 
Published: April 2019

SummaryP4-ATPases are lipid flippases that drive active transport of phospholipids from the exoplasmic or lumenal to the cytosolic leaflets of eukaryotic membranes to maintain their asymmetric lipid composition. The molecular architecture of P4-ATPases and how they work in lipid recognition and transport has remained elusive. Using cryo-electron microscopy we have determined the structures of a P4-ATPase, specifically of theSaccharomyces cerevisiaeDrs2p-Cdc50p, which is a phosphatidylserine and phosphatidylethanolamine specific lipid flippase. Drs2p-Cdc50p is autoinhibited by the Drs2p C-terminal tail and activated by phosphatidylinositol-4 phosphate (PI4P). We present three structures representing an autoinhibited, an intermediate, and a fully activated state. The analysis highlights specific features of P4-ATPases and reveals sites of auto-inhibition and PI4P-dependent activation. We observe the opening of a putative flippase pathway engaging conserved residues Ile508 of transmembrane segment 4 and Lys1018 and polar residues of transmembrane segment 5 in the centre of the lipid bilayer.
Mitotic exit is controlled during anaphase by an Aurora B-Cyclin B1/Cdk1 crosstalk
Authors: Afonso Olga , Cheeseman Liam P. , Ferreira Luísa T. , Morais-de-Sá Eurico , Maiato Helder 
Published: April 2019

SummaryAccording to the prevailing “clock” model, chromosome decondensation and nuclear envelope reassembly during mitotic exit are byproducts of Cdk1 inactivation at the metaphase-anaphase transition, controlled by the spindle assembly checkpoint. However, mitotic exit was recently shown to be a function of chromosome separation during anaphase, assisted by a midzone Aurora B phosphorylation gradient - the “ruler” model. Here we reconciled both models by showing that Cyclin B1 degradation continues during anaphase inDrosophila, mouse and human cells, including primary tissues. This required APC/CCdh1activity, and failure to degrade Cyclin B1 during anaphase prevented mitotic exit in a Cdk1-dependent manner. Cyclin B1 localization and half-life during anaphase depended on kinesin-6, which targets Aurora B to the spindle midzone. Mechanistically, we show that anaphase duration is regulated by Aurora B-mediated phosphorylation of Cyclin B1. We propose that a crosstalk between molecular “rulers” and “clocks” licenses mitotic exit only after proper chromosome separation.
STAT5: A Target of Antagonism by Neurotropic Flaviviruses
Authors: Zimmerman Matthew G. , Bowen James R. , McDonald Circe E. , Young Ellen , Baric Ralph S. , Pulendran Bali , Suthar Mehul S. 
Published: April 2019

AbstractFlaviviruses are a diverse group of arthropod-borne viruses responsible for numerous significant public health threats; therefore, understanding the interactions between these viruses and the human immune response remains vital. Earlier work has found that WNV and ZIKV infect human DCs and can block antiviral immune responses in DCs. Previously, we used mRNA sequencing and weighted gene co-expression network analysis (WGCNA) to define molecular signatures of antiviral DC responses following activation of innate immune signaling (RIG-I, MDA5, or type I IFN signaling) or infection with WNV. Using this approach, we found that several genes involved in T cell co-signaling and antigen processing were not enriched in DCs during WNV infection. Using cis-regulatory sequence analysis, STAT5 was identified as a regulator of DC activation and immune responses downstream of innate immune signaling that was not activated during either WNV or ZIKV infection. Mechanistically, WNV and ZIKV actively blocked STAT5 phosphorylation downstream of RIG-I, IFNβ, and IL-4, but not GM-CSF signaling. Unexpectedly, dengue virus serotypes 1-4 (DENV1-4) and the yellow fever 17D vaccine strain (YFV-17D) did not antagonize STAT5 phosphorylation. In contrast to WNV, ZIKV inhibited JAK1 and TYK2 phosphorylation following type I IFN treatment, suggesting divergent mechanisms used by these viruses to inhibit STAT5 activation. Combined, these findings identify STAT5 as a target of antagonism by specific pathogenic flaviviruses to subvert the immune response in infected DCs.ImportanceFlaviviruses are a diverse group of insect-borne viruses responsible for numerous significant public health threats. Previously, we used a computational biology approach to define molecular signatures of antiviral DC responses following activation of innate immune signaling or infection with WNV. In this work, we identify STAT5 as a regulator of DC activation and antiviral immune responses downstream of innate immune signaling that was not activated during either WNV or ZIKV infection. WNV and ZIKV actively blocked STAT5 phosphorylation downstream of RIG-I, IFNβ, and IL-4, but not GM-CSF signaling. However, other related flaviviruses, dengue virus serotypes 1-4 and yellow fever 17D vaccine strain, did not antagonize STAT5 phosphorylation. Mechanistically, WNV and ZIKV showed differential inhibition of Jak kinases upstream of STAT5, suggesting divergent countermeasures to inhibit STAT5 activation. Combined, these findings identify STAT5 as a target of antagonism by specific pathogenic flaviviruses to subvert antiviral immune responses in human DCs.
Thick perirenal fat predicts the growth pattern of renal cell carcinoma
Authors: Kashiwagi Eiji , Abe Tatsuro , Kinoshita Fumio , Imada Kenjiro , Monji Keisuke , Shiota Masaki , Takeuchi Ario , Inokuchi Junichi , Tatsugami Katsunori , Eto Masatoshi 
Published: April 2019

AbstractObjectiveTo examine the relationship between the direction of renal cell carcinoma growth and the visceral/perirenal fat volume.Patients and Methods: We retrospectively reviewed computed tomography scans of 153 patients with stage 1 renal cell carcinoma who underwent radical or partial nephrectomy in our hospital between January 2013 and July 2016. We calculated the visceral/subcutaneous/perirenal fat volumes using SYNAPSE VINCENT®. Of the 60 patients, the perirenal fat was immunohistochemically stained for leptin, adiponectin, COX-2 and UCP-1, and the association with outward tumor protrusion was evaluated.ResultsOf the 153 cases, 88 had confirmed outward expansion (57.5%), 110 were classed as pT1a (52 and 58 with outer and inner expansion, respectively), 43 were classed as pT1b (36 and 7 with outer and inner expansion, respectively;P<0.0001). Multivariate logistic regression model showed a trend toward significance in pT1b (vs pT1a, [OR] 6.033, 95%CI=2.409-15.108, P=0.0001), perirenal fat percentage >1.0 (vs ≤1.0, [OR] 2.596, 95%CI=1.205-5.591, P=0.014). as independent predictors for outer protrusion. Immunohistochemical staining was positive for UCP-1 expression in 31 out of 41 outgrowth types (75.6%), and all 19 endogenous types (100%;P=0.003).ConclusionsRenal cell carcinoma with thick perirenal fat correlates with an increased likelihood of developing outward tumor protrusion; therefore, fat distribution may affect the development of renal cell carcinoma.
The Neural Consequences of Attentional Prioritization of Internal Representations in Visual Working Memory
Authors: Sahan Muhammet I. , Sheldon Andrew D. , Postle Bradley R. 
Published: April 2019

AbstractAlthough humans can hold multiple items in mind simultaneously, the contents of working memory (WM) can be selectively prioritized to effectively guide behavior in response to rapidly changing exigencies in the environment. Neural evidence for this is seen in studies of dual serial retrocuing of two items held concurrently in visual WM, in which evidence in occipital cortex for the active neural representation of the cued item increases, and evidence for the uncued item decreases, often to levels indistinguishable from empirical baseline. Although this pattern is reminiscent of the effects of selective attention on visual perception, the extent to which more subtle principles of visual attention may also apply to visual working memory remains uncertain. In the present study we explored whether the well-characterized “same-object” benefit in visual target detection, attributed to object-based attention (e.g., Duncan, 1984; Egly, Driver, & Rafal, 1994), may also be observed for information held in visual WM. fMRI data were collected while human subjects (male and female) performed a multi-step serial retrocuing task in which they first viewed two two-dimensional sample stimuli comprised of colored moving dots. After stimulus offset, an initialrelevance cuethen indicated whether both dimensions of only the first or only the second object, or only the color or only the direction-of-motion of both objects, would be relevant for the remainder of the trial, which then proceeded with the standard dual serial retrocuing procedure. Thus, on “object-relevant” trials, the ensuingpriority cuesprompted the selection of one from among two features (“color” or “direction”) bound to the same object, whereas on “feature-relevant” trials thepriority cuesprompted the selection of one from among two features each belonging to a different object. Results of analyses with multivariate inverted encoding models (IEM) revealed a same-object benefit on object-relevant trials: Whereas, on feature-relevant trials, the firstpriority cuetriggered a strengthening of the neural representation of the cued feature and a concomitant weakening-to-baseline of the uncued feature; on object-relevant trials the cued item remained active but did not increase in strength, and the uncued item weakened, but remained significantly elevated throughout the delay period. Of additional interest, on both types of trials the secondpriority cueprompted an active recoding of the uncued item into a different neural representation, perhaps to minimize its ability to interfere with recall of the cued item. Finally, although stimulus-specific representation in parietal and frontal cortex was weak and uneven, these regions closely tracked the higher-order information of which stimulus category was relevant for behavior at all points during the trial, indicating an important role in controlling the prioritization of information in visual working memory.
Heat-triggered remote control of CRISPR-dCas9 for tunable transcriptional modulation
Authors: Gamboa Lena , Phung Erick V. , Li Haoxin , Meyers Jared P. , Kwong Gabriel A. 
Published: April 2019

ABSTRACTEmerging CRISPR technologies are enabling powerful new approaches to control mammalian cell functions, yet the lack of spatially-defined, noninvasive modalities to direct their function limit their potential as biological tools and pose a major challenge for clinical translation. Here we confer remote control of CRISPR-dCas9 activity using thermal gene switches, enabling the dynamic regulation of gene expression using short pulses of heat to modulate transcriptional commands.
Proposing the solar wind-energy-flux hypothesis as a driver of interannual variation in tropical tree reproductive effort tropical tree reproduction
Authors: Hogan J. Aaron , Nytch Christopher J. , Bithorn John E. , Zimmerman Jess K. 
Published: April 2019

AbstractA growing body of research documents how the El Niño Southern Oscillation (ENSO) results in short-term changes in terrestrial environmental conditions, with the potential to drive ecosystem processes as the duration and severity of ENSO events increases with anthropogenic climate change. An ENSO positive phase results in anomalous patterns of rainfall and temperature throughout the tropics that coincide with leaf flush and increased fruit production in tropical forests worldwide. However, our understanding of possible mechanisms underlying this natural phenomenon is limited. Furthermore, flowering in tropical trees anticipates ENSO development, motivating the continued search for a global phenological cue for tropical angiosperm reproduction. We propose the solar energy flux hypothesis: that a physical energy influx in the Earth’s upper atmosphere and magnetosphere generated by a positive anomaly in the solar wind preceding ENSO development, cues tropical trees to increase allocation of resources to reproduction. We show that from 1994-2013, the solar wind energy flux into the Earth’s magnetosphere (Ein) is more strongly correlated with the number of trees in fruit or flower in a Puerto Rican wet forest than the Niño 3.4 climate index, despite Niño 3.4 being a previously identified driver of interannual increases in reproduction. We discuss the idea that changes in the global magnetosphere and thermosphere conditions via solar wind-effects on global atmospheric circulation, principally a weaker Walker circulation, cue interannual increases tropical tree reproduction. This may be a mechanism that synchronizes the reproductive output of the tropical trees to changes in environmental conditions that coincide with ENSO. Thus, space weather patterns may help explain terrestrial biological phenomena that occur at quasi-decadal scales.
Genome-wide Associations of Flavivirus Capsid Proteins
Authors: Boon P. L.S. , Martins A. S. , Enguita F. J. , Lim X. N. , Santos N. C. , Matsudaira P. T. , Martins I. C. , Yue W. , Bond P. J. , Huber R. G. 
Published: April 2019

AbstractDengue virus (DENV) and Zika virus (ZIKV) are both positive sense single-stranded RNA viruses. They are packaged within the virion with a capsid (C) protein to form the nucleocapsid. Based on cryo-electron microscopy imaging, the nucleocapsid has been described as lacking symmetry, whilst there is distinguishable separation of the C proteins from the viral RNA (vRNA) genome. Here, to elucidate the architecture of the nucleocapsid of DENV serotype 2 and ZIKV, we used a nuclease digestion assay and next-generation sequencing to map the respective vRNA genome wide association with the C proteinin vitro. The C protein exhibited non-uniform binding along the vRNA, and as C protein concentration increased, the normalized read counts also increased. A saturation point of 1:100 (vRNA:C protein monomers) was found, and binding regions showed variable saturation patterns. We also observed that C protein had a preference for G-rich sequences for both viruses. Taken together, we demonstrate that the DENV 2 and ZIKV C proteins bind vRNA in a non-uniform manner with distinct patterns of association.Singificance StatementOur study demonstrates that flavivirus capsid proteins associate with the viral genome at specific sites rather than in a uniform manner as commonly expected. We estimate the number of capsid proteins binding to a single genomic RNA. We proceed to locate the capsid binding sites along the viral genomes of Dengue and Zika viruses. We characterize the binding sites in terms of affinity and analyze the nucleotide composition and sequence motifs at binding sites. We cross-reference binding sites against SHAPE reactivity data corresponding to local RNA secondary structure, which allows us to identify structural motifs of capsid binding sites. As capsid proteins are essential for viral packaging, these interactions may form attractive targets for therapeutic intervention.
An Integrated Platform for High-Throughput Nanoscopy
Authors: Barentine Andrew E S , Lin Yu , Courvan Edward M , Kidd Phylicia , Liu Miao , Balduf Leonhard , Phan Timy , Rivera-Molina Felix , Grace Michael R , Marin Zach , Lessard Mark , Chen Juliana Rios , Wang Siyuan , Neugebauer Karla M , Bewersdorf Joerg , Baddeley David 
Published: April 2019

AbstractDiffraction-unlimited single-molecule techniques like STORM and (F)PALM enable three-dimensional (3D) fluorescence imaging at tens of nanometer resolution and are invaluable to investigate sub-cellular organization. The multitude of camera frames required to reconstruct a super-resolved image limits the typical throughput of these techniques to tens of cells per day, rendering these methods incompatible with large-scale cell biological or clinical application. STORM acquisition rates can be increased by over an order of magnitude, however the data volumes of about 40 TB a day and concomitant analysis burdens exceed the capacity of existing workflows. Here we present an integrated platform which transforms SMLM from a trick-pony technique into a work horse for cell biology. We leverage our developments in microscopy-specific data compression, distributed storage, and distributed analysis to automatically perform real-time localization analysis, which enable SMLM at throughputs of 10,000 cells a day. We implemented these advances in a fully-integrated environment that supports a highly-flexible architecture for distributed analysis, enabling quickly- and graphically-reconfigurable analyses to be automatically initiated from the microscope during acquisition, remotely executed, and even feedback and queue new acquisition tasks on the microscope. We demonstrate the utility of this framework by imaging hundreds of cells per well in multi-well sample formats. Our platform, the PYthon-Microscopy Environment (PYME), is easily configurable for hardware control on custom microscopes, and includes a plugin framework so users can readily extend all components of their imaging, visualization, and analysis pipeline. PYME is cross-platform, open source, and efficiently puts high-caliber visualization and analysis tools into the hands of both microscope developers and users.
Dissecting the transcriptomic basis of phenotypic evolution in an aquatic keystone grazer
Authors: Frisch Dagmar , Becker Dörthe , Wojewodzic Marcin W. 
Published: April 2019

AbstractCultural eutrophication is one of the largest threats to aquatic ecosystems with devastating ecological and economic consequences. AlthoughDaphnia, a keystone grazer crustacean, can mitigate some negative effects of eutrophication in freshwater habitats, it is itself affected by changes in nutrient composition. Previous studies have shown evolutionary adaptation ofDaphniato environmental change, including high phosphorus levels. While phosphorus is an essential macronutrient, it negatively affectsDaphnialife history when present in excessive concentrations. Here, we map weighted gene co-expression networks to phosphorus-related phenotypic traits in centuries-old ancestralDaphniaand their modern descendants, contrasting pre- and post-eutrophication environments. We find that evolutionary fine-tuning of transcriptional responses is manifested at a basic (cellular) phenotypic level, and is strongly correlated to an evolved plasticity of gene expression. At a higher phenotypic level, this contributes to the maintenance of physiological homeostasis, and a robust preservation of somatic phosphorus concentration.