bluuebunny/crossref_metadata_2025 huggingface dataset:
The Dialysis Procedure Triggers Autonomic Imbalance and Cardiac Arrhythmias: Insights from Continuous 14-day ECG Monitoring
Authors: Rogovoy Nichole M. , Howell Stacey J. , Lee Tiffany L. , Hamilton Christopher , Perez-Alday Erick A. , Kabir Muammar M. , Li-Pershing Yin , Zhang Yanwei , Kim Esther D. , Fitzpatrick Jessica , Monroy-Trujillo Jose M. , Estrella Michelle M. , Sozio Stephen M. , Jaar Bernard G. , Parekh Rulan S. , Tereshchenko Larisa G.
Published: April 2019

Background

In end-stage kidney disease the dialytic cycle relates to the rate of sudden cardiac death. We hypothesized that circadian, dialytic cycles, paroxysmal arrhythmias, and cardiovascular risk factors are associated with periodic changes in heart rate and heart rate variability (HRV) in incident dialysis patients.

Methods

We conducted a prospective ancillary study of the Predictors of Arrhythmic and Cardiovascular Risk in End Stage Renal Disease cohort (n=28; age 54±13 y; 57% men; 96% black; 33% with a history of structural heart disease; left ventricular ejection fraction 70±9%). Continuous ECG monitoring was performed using an ECG patch (Zio Patch, iRhythm) and short-term HRV was measured for three minutes every hour. HRV was measured by root mean square of the successive normal-to-normal intervals (rMSSD), high and low frequency power, Poincaré plot, and sample and Renyi entropy.

Results

Arrhythmias were detected in 46% (n=13). Non-sustained ventricular tachycardia (VT) was more frequent during dialysis or within 6 hours post-dialysis, as compared to pre-or between-dialysis (63% vs. 37%, P=0.015), whereas supraventricular tachycardia was more frequent pre-/ between-dialysis, as compared to during-/ post-dialysis (84% vs. 16%, P=0.015). In adjusted for cardiovascular disease and its risk factors autoregressive conditional heteroscedasticity panel (ARCH) model, VT events were associated with increased heart rate by 11.2 (95%CI 10.1-12.3) bpm (P<0.0001). During regular dialytic cycle, rMSSD demonstrated significant circadian pattern (Mesor 10.6(0.9-11.2) ms; Amplitude 1.5(1.0-3.1) ms; Peak at 02:01(20:22-03:16) am; P<0.0001), which was abolished on a second day interdialytic extension (adjusted ARCH trend for rMSSD −1.41(−1.67 to −1.15) ms per 24h; P<0.0001).

Conclusion

Cardiac arrhythmias associate with dialytic phase. Regular dialytic schedule preserves physiological circadian rhythm, but the second day without dialysis is characterized by parasympathetic withdrawal and a steady increase in sympathetic predominance.

Subject Terms

Arrhythmias, Autonomic Nervous System, Electrocardiology (ECG), Treatment.
Interdisciplinary and disciplinary identities: towards a theory of forms of knowledge change1
Authors: van den Besselaar Peter
Published: April 2019

The concept of interdisciplinarity lacks theoretical understanding, and consequently, the number of indicators for interdisciplinarity is booming: out of field citations, betweenness centrality, or the set coherence, diversity, mediation, to mention a few. However, these indicators focus on characteristics of papers and journals, without referring clearly to the processes of knowledge production, communication and stabilization. Without understanding of the nature of interdisciplinarity and its various forms, the choice of indicators seems rather arbitrary. In this paper we argue that interdisciplinarity is one of the forms of development of research fields. We will show that interdisciplinarity is a temporary phase in knowledge dynamics. New fields emerge at the boundaries of existing fields as multidisciplinary research activities, and either develop through an interdisciplinary phase into a ‘new’ discipline’, or remain multidisciplinary for a while and generally disappear.

We use the analysis of journal-journal citation relations to map the identity and development of disciplinary, multidisciplinary and interdisciplinary research fields. A comparison results in three types of identities: (1) disciplinary fields, (2) interdisciplinarity as a developmental phase from multidisciplinary to disciplinary fields, and (3) unstable temporal multidisciplinary research topics at the boundaries between research fields. We conclude that the main difference between a mature interdisciplinary field and ‘normal’ disciplinary fields is that the former is newer than the latter. We propose to focus on change in the research landscape, instead of on indicators for what is only one (early or long term unstable) stage of interdisciplinarity. The mapping approach can be used to identify the nature of cognitive change in general, such as the emergence, growth, differentiation, merger, and decline of research fields.
Exploring dimension-reduced embeddings with Sleepwalk
Authors: Ovchinnikova Svetlana , Anders Simon
Published: April 2019

Dimension-reduction methods, such as t-SNE or UMAP, are widely used when exploring high-dimensional data describing many entities, e.g., RNA-seq data for many single cells. However, dimension reduction is commonly prone to introducing artefacts, and we hence need means to see where a dimension-reduced embedding is a faithful representation of the local neighbourhood and where it is not.

We present Sleepwalk, a simple but powerful tool that allows the user to interactively explore an embedding, using colour to depict original or any other distances from all points to the cell under the mouse cursor. We show how this approach not only highlights distortions, but also reveals otherwise hidden characteristics of the data, and how Sleep-walk’s comparative modes help integrate multi-sample data and understand differences between embedding and preprocessing methods. Sleepwalk is a versatile and intuitive tool that unlocks the full power of dimension reduction and will be of value not only in single-cell RNA-seq but also in any other area with matrix-shaped big data.
Natural hypothalamic circuit dynamics underlying object memorization
Authors: Kosse Christin , Burdakov Denis
Published: April 2019

Memorizing encountered objects is fundamental for normal life, but the underlying natural brain activity remains poorly understood. The hypothalamus is historically implicated in memory disorders, but whether and how its endogenous real-time activity affects object memorization remains unknown. We found that upon self-initiated object encounters, hypothalamic melanin-concentrating hormone (MCH) neurons emit dynamic, object-encounter-associated signals encoding object novelty. Optosilencing of these signals, performed in closed-loop with object encounters selectively during object memory acquisition, prevented the ability to recognize the previously encountered objects. Optogenetic and chemogenetic connectivity analyses demonstrated that local GAD65 neurons form an inhibitory GAD65→MCH microcircuit that controls the object-encounter-associated MCH cell signals. GAD65 cell optosilencing during object memory acquisition enhanced future object recognition through MCH-receptor-dependent pathways. These results provide causal evidence that natural, object-associated signals in genetically-distinct but interacting hypothalamic neurons differentially control whether the brain forms object memories.
Macroevolutionary integration of phenotypes within and across ant worker castes
Authors: Friedman Nicholas R. , Bennet Beatrice Lecroq , Fischer Georg , Sarnat Eli M. , Huang Jen-Pan , Lacey Knowles L. , Economo Evan P.
Published: April 2019

Phenotypic traits are often integrated into evolutionary modules: sets of organismal parts that evolve together. In social insect colonies the concepts of integration and modularity apply to sets of traits both within and among functionally and phenotypically differentiated castes. On macroevolutionary timescales, patterns of integration and modularity within and across castes can be clues to the selective and ecological factors shaping their evolution and diversification. We develop a set of hypotheses describing contrasting patterns of worker integration and apply this framework in a broad (246 species) comparative analysis of major and minor worker evolution in the hyperdiverse ant genusPheidole. Using geometric morphometrics in a phylogenetic framework, we inferred fast and tightly integrated evolution of mesosoma shape between major and minor workers, but slower and more independent evolution of head shape between the two worker castes. Thus,Pheidoleworkers are evolving as a mixture of intra- and inter-caste integration and rate heterogeneity. The decoupling of homologous traits across worker castes may represent an important process facilitating the rise of social complexity.
A data-driven, meaningful, easy to interpret, population-independent accelerometer outcome variable for global surveillance
Authors: Rowlands Alex V. , Sherar Lauren B. , Fairclough Stuart J. , Yates Tom , Edwardson Charlotte L. , Harrington Deirdre M. , Davies Melanie J. , Munir Fehmidah , Khunti Kamlesh , Stiles Victoria H.
Published: April 2019

Background

Accelerometer-driven physical activity guidelines are not available, likely due to the lack of consensus on meaningful and interpretable accelerometer outcomes. The aim of this paper is to demonstrate how a data-driven accelerometer metric, the acceleration above which a person’s most active minutes are accumulated, can a) quantify the prevalence of meeting current physical activity guidelines for global surveillance and b) moving forward, could inform accelerometer-driven physical activity guidelines. Unlike cut-point methods, the metric is population-independent (e.g. age) and comparable across datasets.

Methods

Secondary data analyses were carried out on five datasets using wrist-worn accelerometers: children (N=145), adolescent girls (N=1669), office workers (N=114), pre- (N=1218) and post- (N=1316) menopausal women, and adults with type 2 diabetes (N=475). Open-source software (GGIR) was used to generate the magnitude of acceleration above which a person’s most active 60, 30 and 2 minutes are accumulated: M60ACC; M30ACCand M2ACC, respectively.

Results

The proportion of participants with M60ACC(children) and M30ACC(adults) values higher than accelerations indicative of brisk walking (i.e., moderate-to-vigorous physical activity) ranged from 17-68% in children and 15%-81% in adults, tending to decline with age. The proportion of pre-and post-menopausal women with M2ACCvalues indicative of running and thus meeting recently presented thresholds for bone health ranged from 6-13%.

Conclusion

These metrics can be used for global surveillance of physical activity, including assessing prevalence of meeting the current physical activity guidelines, across the lifespan. Translation of acceleration magnitudes into indicative activities provides a public health friendly interpretation of results. As accelerometer and corresponding health data accumulate it will be possible to interpret the metrics relative to age- and sex-specific norms and derive evidence-based physical activity guidelines directly from accelerometer data for use in future global surveillance. This is where the key advantages of these metrics lie.
A microtubule-mediated mechanical feedback controls leaf blade development in three dimensions
Authors: Zhao Feng , Du Fei , Oliveri Hadrien , Zhou Lüwen , Ali Olivier , Chen Wenqian , Feng Shiliang , Wang Qingqing , Lü Shouqin , Long Mian , Schneider René , Sampathkumar Arun , Godin Christophe , Traas Jan , Jiao Yuling
Published: April 2019

Many plant species have thin leaf blades, which is an important adaptation that optimizes the exchanges with the environment. Here, we provide evidence that their three-dimensional geometry is governed by microtubule alignment along mechanical stress patterns in internal walls. Depending on the primary shape of the primordium, this process has the potential to amplify an initial degree of flatness, or promote the formation of nearly axisymmetric, mostly elongating organs, such as stems and roots. This mechanism may explain leaf evolution from branches, which is alternative to Zimmermann’s influential, but widely questioned,telometheory.

One Sentence Summary

Mechanical feedback controls leaf development in three dimensions
Structural basis for inhibition of human primase by arabinofuranosyl nucleoside analogues Fludarabine and Vidarabine
Authors: Holzer Sandro , Rzechorzek Neil J. , Short Isobel R. , Jenkyn-Bedford Michael , Pellegrini Luca , Kilkenny Mairi L.
Published: April 2019

Nucleoside analogues are widely used in clinical practice as chemotherapy drugs. Arabinose nucleoside derivatives such as Fludarabine are effective in the treatment of patients with acute and chronic leukemias and non-Hodgkin lymphomas. Although nucleoside analogues are generally known to function by inhibiting DNA synthesis in rapidly proliferating cells, the identity of theirin vivotargets and mechanism of action are often not known in molecular detail. Here we provide a structural basis for inhibition by arabinose nucleotides of human primase, the DNA-dependent RNA polymerase responsible for initiation of DNA synthesis in DNA replication. Our data suggest ways in which the chemical structure of Fludarabine could be modified to improve its specificity and affinity towards primase, possibly leading to less toxic and more effective therapeutic agents.
Toxicity drives facilitation between four bacterial species
Authors: Piccardi Philippe , Vessman Björn , Mitri Sara
Published: April 2019

Competition between microbes is extremely common, with many investing in a wide range of mechanisms to harm other strains and species. Yet positive interactions between species have also been documented. What makes species help or harm each other is currently unclear. Here, we studied the interactions between four bacterial species capable of degrading Metal-Working Fluids (MWF), an industrial coolant and lubricant, which contains growth substrates as well as toxic biocides. We were surprised to find only positive or neutral interactions between the four species. Using mathematical modeling and further experiments, we show that positive interactions in this community are likely due to the toxicity of MWF, whereby each species’ detoxification benefited the others by facilitating their survival, such that they could grow and degrade MWF better when together. The addition of nutrients, the reduction of toxicity or the addition of more species instead resulted in competitive behavior. Our work provides support to the stress gradient hypothesis by showing how harsh, toxic environments can strongly favor facilitation between microbial species and mask underlying competitive interactions.
Endocrine, metabolic, and endocannabinoid alterations in rats exhibiting high anxiety-related behaviors
Authors: Vega-Torres Julio David , Kalyan-Masih Priya , Argueta Donovan A. , DiPatrizio Nicholas V. , Figueroa Johnny D.
Published: April 2019

Anxiety disorders are major risk factors for obesity. However, the mechanisms accounting for this susceptibility remain unclear. Animal models have proved to be useful tools for understanding the role of emotional functioning in the development and maintenance of metabolic alterations implicated in obesity. Here we sought to determine the predictive value of behavioral indices of anxiety for hormonal and metabolic imbalances in rats. Adult Lewis rats were screened on the elevated plus maze (EPM). K-means clustering was used to divide the rats into two groups based on their anxiety index in the EPM: low (LA) and high anxiety (HA) rats. This proxy of anxiety combines individual EPM parameters and accepted ratios into a single score. Four weeks later, we measured markers of endocrine and metabolic function. We found that relative LA rats, the HA rats exhibited reduced latencies to exit a modified light-dark conflict test. Our results show that the HA rats displayed increased corticosterone levels when compared to LA rats. Furthermore, the HA rats weighted more and exhibited an enhanced glycemic response to exogenously administered glucose during the glucose tolerance test, indicating glucose intolerance. Notably, when compared to LA rats, the HA rats showed higher circulating levels of the endogenous cannabinoid, 2-arachidonoyl-sn-glycerol (2-AG). Together, these data indicate that patterns of emotional reactivity associated with anxiety may share common pathological pathways with metabolic complications implicated in obesity. Uncovering metabolic risk factors for anxiety disorders have the potential to strongly impact how we treat mental illnesses.

Objective

To test the hypothesis that indices of anxiety in the elevated plus maze have predictive value for alterations implicated in obesity, which include heightened emotional reactivity, and dysregulated corticosterone, glucose metabolism, and circulating endocannabinoid levels.
BreakCA, a method to discover indels using ChIP-seq and ATAC-seq reads, finds recurrent indels in regulatory regions of neuroblastoma genomes
Authors: Sen Arko , Tyndale Sélène T. , Fu Yi , Erikson Galina , McVicker Graham
Published: April 2019

Most known cancer driver mutations are within protein coding regions of the genome, however, there are several important examples of oncogenic non-coding regulatory mutations. We developed a method to identify insertions and deletions (indels) in regulatory regions using aligned reads from chromatin immunoprecipitation followed by sequencing (ChIP-seq) or the assay for transposase-accessible chromatin (ATAC-seq). Our method, which we call BreakCA for Breaks in Chromatin Accessible regions, allows non-coding indels to be discovered in the absence of whole genome sequencing data, out-performs popular variant callers such as the GATK-HaplotypeCaller and VarScan2, and detects known oncogenic regulatory mutations in T-cell acute lymphoblastic leukemia cell lines. We apply BreakCA to identify indels in H3K27ac ChIP-seq peaks in 23 neuroblastoma cell lines and, after removing common germline variants, we identify 23 rare germline or somatic indels that occur in multiple neuroblastoma cell lines. Among them, 4 indels are candidate oncogenic drivers that are present in 4 or 5 cell lines, absent from the genome aggregation database of over 15,000 whole genome sequences, and within the promoters or first introns of known genes (PHF21A, ADAMTS19, GPR85andRALGDS). In addition, we observe a rare 7bp germline deletion in two cell lines, which is associated with high expression of the histone demethylaseKDM5B. Overexpression ofKDM5Bis prognostic for many cancers and further characterization of this indel as a potential oncogenic risk factor is therefore warranted.
Interplay between gene nucleotide composition bias and splicing
Authors: Lemaire Sébastien , Fontrodona Nicolas , Claude Jean-Baptiste , Polvèche Hélène , Aubé Fabien , Modolo Laurent , Bourgeois Cyril F. , Mortreux Franck , Auboeuf Didier
Published: April 2019

To characterize the rules governing exon recognition during splicing, we analysed dozens of RNA-seq datasets and identified ~3,200 GC-rich exons and ~4,000 AT-rich exons whose inclusion depends on different sets of splicing factors. We show that GC-rich exons have predicted RNA secondary structures at 5’-ss, and are dependent on U1 snRNP–associated proteins. In contrast, AT-rich exons have a large number of branchpoints and SF1-or U2AF2-binding sites and are dependent on U2 snRNP–associated proteins. Nucleotide composition bias also influences local chromatin organization, with consequences for exon recognition during splicing. As the GC content of exons correlates with that of their hosting genes, isochores and topologically-associated domains, we propose that regional nucleotide composition bias leaves a local footprint at the exon level and induces constraints during splicing that can be alleviated by local chromatin organization and recruitment of specific splicing factors. Therefore, nucleotide composition bias establishes a direct link between genome organization and local regulatory processes, like alternative splicing.
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

Objective

This 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.

Methods

The 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.

Results

ε-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.

Conclusions

ε-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.

Importance

The 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

P4-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

According 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

Flaviviruses 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.

Importance

Flaviviruses 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

Objective

To 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.

Results

Of 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).

Conclusions

Renal 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

Although 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

Emerging 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

A 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

Dengue 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 Statement

Our 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

Diffraction-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

Cultural 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.
Evaluation of parameters affecting performance and reliability of machine learning-based antibiotic susceptibility testing from whole genome sequencing data
Authors: Hicks Allison L. , Wheeler Nicole , Sánchez-Busó Leonor , Rakeman Jennifer L. , Harris Simon R. , Grad Yonatan H.
Published: April 2019

Prediction of antibiotic resistance phenotypes from whole genome sequencing data by machine learning methods has been proposed as a promising platform for the development of sequence-based diagnostics. However, there has been no systematic evaluation of factors that may influence performance of such models, how they might apply to and vary across clinical populations, and what the implications might be in the clinical setting. Here, we performed a meta-analysis of seven large Neisseria gonorrhoeae datasets, as well as Klebsiella pneumoniae and Acinetobacter baumannii datasets, with whole genome sequence data and antibiotic susceptibility phenotypes using set covering machine classification, random forest classification, and random forest regression models to predict resistance phenotypes from genotype. We demonstrate how model performance varies by drug, dataset, resistance metric, and species, reflecting the complexities of generating clinically relevant conclusions from machine learning-derived models. Our findings underscore the importance of incorporating relevant biological and epidemiological knowledge into model design and assessment and suggest that doing so can inform tailored modeling for individual drugs, pathogens, and clinical populations. We further suggest that continued comprehensive sampling and incorporation of up-to-date whole genome sequence data, resistance phenotypes, and treatment outcome data into model training will be crucial to the clinical utility and sustainability of machine learning-based molecular diagnostics.

Author Summary

Machine learning-based prediction of antibiotic resistance from bacterial genome sequences represents a promising tool to rapidly determine the antibiotic susceptibility profile of clinical isolates and reduce the morbidity and mortality resulting from inappropriate and ineffective treatment. However, while there has been much focus on demonstrating the diagnostic potential of these modeling approaches, there has been little assessment of potential caveats and prerequisites associated with implementing predictive models of drug resistance in the clinical setting. Our results highlight significant biological and technical challenges facing the application of machine learning-based prediction of antibiotic resistance as a diagnostic tool. By outlining specific factors affecting model performance, our findings provide a framework for future work on modeling drug resistance and underscore the necessity of continued comprehensive sampling and reporting of treatment outcome data for building reliable and sustainable diagnostics.
Comparative transcriptomics analyses across species, organs and developmental stages reveal functionally constrained lncRNAs
Authors: Darbellay Fabrice , Necsulea Anamaria
Published: April 2019

Background

Transcription of long non-coding RNAs (lncRNAs) is pervasive, but their functionality is disputed. As a class, lncRNAs show little selective constraint and negligible phenotypic effects upon perturbation. However, key biological roles were demonstrated for individual lncRNAs. Most validated lncRNAs were implicated in gene expression regulation, in pathways related to cellular pluripotency, differentiation and organ morphogenesis, suggesting that functional lncRNAs may be more abundant in embryonic development, rather than in adult organs.

Results

Here, we perform a multi-dimensional comparative transcriptomics analysis, across five developmental time-points (two embryonic stages, newborn, adult and aged individuals), four organs (brain, kidney, liver and testes) and three species (mouse, rat and chicken). Overwhelmingly, lncRNAs are preferentially expressed in adult and aged testes, consistent with the presence of permissive transcription during spermatogenesis. LncRNAs are often differentially expressed among developmental stages and are less abundant in embryos and newborns compared to adult individuals, in agreement with a requirement for tighter expression control and less tolerance for noisy transcription early in development. However, lncRNAs expressed during embryonic development show increased levels of evolutionary conservation, both in terms of primary sequence and of expression patterns, and in particular at their promoter regions. We find that species-specific lncRNA transcription is frequent for enhancer-associated loci and occurs in parallel with expression pattern changes for neighboring protein-coding genes.

Conclusions

We show that functionally constrained lncRNA loci are enriched in developing organ transcriptomes, and propose that many of these loci may function in an RNA-independent manner.
Machine learning prediction of emesis and gastrointestinal state in ferrets
Authors: Nanivadekar Ameya C. , Miller Derek M. , Fulton Stephanie , Wong Liane , Ogren John , Chitnis Girish , McLaughlin Bryan , Zhai Shuyan , Fisher Lee E. , Yates Bill J. , Horn Charles C.
Published: April 2019

Although electrogastrography (EGG) could be a critical tool in the diagnosis and treatment of patients with gastrointestinal (GI) disease, it remains under-utilized. The lack of spatial and temporal resolution using current EGG methods presents a significant roadblock to more widespread usage. Human and preclinical studies have shown that GI myoelectric electrodes can record signals containing significantly more information than can be derived abdominal surface electrodes. The current study sought to assess the efficacy of multi-electrode arrays, surgically implanted on the serosal surface of the GI tract, from gastric fundus to duodenum, in recording myoelectric signals. It also examines the potential for machine learning algorithms to predict functional states, such as retching and emesis, from GI signal features. Studies were performed using ferrets, a gold standard model for emesis testing. Our results include simultaneous recordings from up to six GI recording sites in both anesthetized and chronically implanted free-moving ferrets. Testing conditions to produce different gastric states included gastric distension, intragastric infusion of emetine (a prototypical emetic agent), and feeding. Despite the observed variability in GI signals, machine learning algorithms, including k nearest neighbors and support vector machines, were able to detect the state of the stomach with high overall accuracy (>80%). The present study is the first demonstration of machine learning algorithms to detect the physiological state of the stomach and onset of retching and could provide insight into methodologies to treat GI diseases and control symptoms such as nausea and vomiting.