bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hyperglycemia enhances cancer immune evasion by inducing alternative macrophage polarization through increased O-GlcNAcylation
Authors: Mantuano Natália Rodrigues , Stanczak Michal A. , de Araújo Oliveira Isadora , Kirchhammer Nicole , Filardy Alessandra , Monaco Gianni , Santos Ronan Christian , Fonseca Agatha Carlos , Fontes Miguel , de Souza Bastos César , Dias Wagner B. , Zippelius Alfred , Todeschini Adriane R. , Läubli Heinz 
Published: November 2019

SummaryDiabetes mellitus (DM) significantly increases the risk for cancer and cancer progression. Hyperglycemia is the defining characteristic of DM and tightly correlates with a poor prognosis in cancer patients. The hexosamine biosynthetic pathway (HBP) is emerging as a pivotal cascade linking high glucose, tumor progression and impaired immune function. Here we show that enhanced glucose flow through the HBP drives cancer progression and immune evasion by increasing O-GlcNAcylation in tumor-associated macrophages (TAMs). Increased O-GlcNAc skewed macrophage polarization to a M2-like phenotype. HBP or O-GlcNAcylation inhibition reprogrammed TAMs to an anti-tumoral phenotype. Finally, we found an upregulation of M2 markers on TAMs in DM2 patients with colorectal cancer compared to non-diabetic normoglycemic patients. Our results provide evidence for a new and targetable mechanism of cancer immune evasion in patients with hyperglycemia, advocating for strict control of hyperglycemia in cancer patients.SignificanceHyperglycemia increases O-GlcNAc levels in TAMs, programing them to a pro-tumorigenic phenotype (M2-like), contributing to cancer progression. Inhibition of O-GlcNAcylation could therefore be used to reprogram intratumoral macrophages to an anti-tumoral phenotype.
Asymmetrical reliability of the Alda Score favours a dichotomous representation of lithium responsiveness
Authors: Nunes Abraham , Trappenberg Thomas , Alda Martin 
Published: November 2019

AbstractThe Alda score is commonly used to quantify lithium responsiveness in bipolar disorder. Most often, this score is dichotomized into “responder” and “non-responder” categories, respectively. This practice is often criticized as inappropriate, since continuous variables are thought to invariably be “more informative” than their dichotomizations. We therefore investigated the degree of informativeness across raw and dichotomized versions of the Alda score, using data from a published study of the scale’s inter-rater reliability (n=59 raters of 12 standardized vignettes each). After learning a generative model for the relationship between observed and ground truth scores (the latter defined by a consensus rating of the 12 vignettes), we show that the dichotomized scale is more robust to inter-rater disagreement than the raw 0-10 scale. Further theoretical analysis shows that when a measure’s reliability is stronger at one extreme of the continuum—a scenario which has received little-to-no statistical attention, but which likely occurs for the Alda score ≥ 7—dichotomization of a continuous variable may be more informative concerning its ground truth value, particularly in the presence of noise. Our study suggests that research employing the Alda score of lithium responsiveness should continue using the dichotomous definition, particularly when data are sampled across multiple raters.
Using structural connectivity to augment community structure in EEG functional connectivity
Authors: Glomb Katharina , Mullier Emeline , Carboni Margherita , Rubega Maria , Iannotti Giannarita , Tourbier Sebastien , Seeber Martin , Vulliemoz Serge , Hagmann Patric 
Published: November 2019

AbstractRecently, EEG recording techniques and source analysis have improved, making it feasible to tap into fast network dynamics. Yet, analyzing whole-cortex EEG signals in source space is not standard, partly because EEG suffers from volume conduction: Functional connectivity (FC) reflecting genuine functional relationships is impossible to disentangle from spurious FC introduced by volume conduction. Here, we investigate the relationship between white matter structural connectivity (SC) and large scale network structure encoded in EEG-FC. We start by confirming that FC (power envelope correlations) is predicted by SC beyond the impact of Euclidean distance, in line with the assumption that SC mediates genuine FC. We then use information from white matter structural connectivity (SC) in order to smooth the EEG signal in the space spanned by graphs derived from SC. Thereby, FC between nearby, structurally connected brain regions increases while FC between non-connected regions remains unchanged, resulting in an increase in genuine, SC-mediated FC. We analyze the induced changes in FC, assessing the resemblance between EEG- and volume-conduction-free fMRI-FC, and find that smoothing increases resemblance in terms of overall correlation and community structure. This result suggests that our method boosts genuine FC, an outcome that is of interest for many EEG network neuroscience questions.Author summaryIn this study, we combine high-density EEG recorded during resting state with white matter connectivity obtained from diffusion MRI and fiber tracking. We leverage the additional information contained in the structural connectome towards augmenting the source level EEG functional connectivity. In particular, it is known - and confirmed in this study - that the activity of brain regions that possess a direct anatomical connection is, on average, more strongly correlated than that of regions that have no such direct link. We use the structural connectome to define a graph and smooth the source reconstructed EEG signal in the space spanned by this graph. We compare the resulting “filtered” signal correlation matrices to those obtained from fMRI and find that such “graph filtering” improves the agreement between EEG and fMRI functional connectivity structure. This suggests that structural connectivity can be used to attenuate some of the limitations imposed by volume conduction.
Critical nodes reveal peculiar features of human essential genes and protein interactome
Authors: Celestini Alessandro , Cianfriglia Marco , Mastrostefano Enrico , Palma Alessandro , Castiglione Filippo , Tieri Paolo 
Published: November 2019

AbstractNetwork-based ranking methods (e.g., centrality analysis) have found extensive use in systems biology and network medicine for the prediction of essential proteins, for the prioritization of drug targets candidates in the treatment of several pathologies and in biomarker discovery, and for human disease genes identification. We here studied the connectivity of the human protein-protein interaction network (i.e., the interactome) to find the nodes whose removal has the heaviest impact on the network, i.e., maximizes its fragmentation. Such nodes are known as Critical Nodes (CNs). Specifically, we implemented a Critical Node Heuristic (CNH) and compared its performance against other four heuristics based on well known centrality measures. To better understand the structure of the interactome, the CNs’ role played in the network, and the different heuristics’ capabilities to grasp biologically relevant nodes, we compared the sets of nodes identified as CNs by each heuristic with two experimentally validated sets of essential genes, i.e., the genes whose removal impact on a given organism’s ability to survive. Our results show that classical centrality measures (i.e., closeness centrality, degree) found more essential genes with respect to CNH on the current version of the human interactome, however the removal of such nodes does not have the greatest impact on interactome connectivity, while, interestingly, the genes identified by CNH show peculiar characteristics both from the topological and the biological point of view. Finally, even if a relevant fraction of essential genes is found via the classical centrality measures, the same measures seem to fail in identifying the whole set of essential genes, suggesting once again that some of them are not central in the network, that there may be biases in the current interaction data, and that different, combined graph theoretical and other techniques should be applied for their discovery.
A Diploid Assembly-based Benchmark for Variants in the Major Histocompatibility Complex
Authors: Chin Chen-Shan , Wagner Justin , Zeng Qiandong , Garrison Erik , Garg Shilpa , Fungtammasan Arkarachai , Rautiainen Mikko , Marschall Tobias , Dilthey Alexander T , Zook Justin M. 
Published: November 2019

AbstractWe develop the first human benchmark derived from a diploid assembly for the openly-consented Genome in a Bottle/Personal Genome Project Ashkenazi son (HG002). As a proof-of-principle, we focus on a medically important, highly variable, 5 million base-pair region - the Major Histocompatibility Complex (MHC). Most human genomes are characterized by aligning individual reads to the reference genome, but accurate long reads and linked reads now enable us to construct base-level accurate, phased de novo assemblies from the reads. We assemble a single haplotig (haplotype-specific contig) for each haplotype, and align reads back to each assembled haplotig to identify two regions of lower confidence. We align the haplotigs to the reference, call phased small and structural variants, and define the first small variant benchmark for the MHC, covering 21496 small variants in 4.58 million base-pairs (92 % of the MHC). The assembly-based benchmark is 99.95 % concordant with a draft mapping-based benchmark from the same long and linked reads within both benchmark regions, but covers 50 % more variants outside the mapping-based benchmark regions. The haplotigs and variant calls are completely concordant with phased clinical HLA types for HG002. This benchmark reliably identifies false positives and false negatives from mapping-based callsets, and enables performance assessment in regions with much denser, complex variation than regions covered by previous benchmarks. These methods demonstrate a path towards future diploid assembly-based benchmarks for other complex regions of the genome.
On the impact of contaminants on the accuracy of genome skimming and the effectiveness of exclusion read filters
Authors: Rachtman Eleonora , Balaban Metin , Bafna Vineet , Mirarab Siavash 
Published: November 2019

AbstractThe ability to detect the identity of a sample obtained from its environment is a cornerstone of molecular ecological research. Thanks to the falling price of shotgun sequencing, genome skimming, the acquisition of short reads spread across the genome at low coverage, is emerging as an alternative to traditional barcoding. By obtaining far more data across the whole genome, skimming has the promise to increase the precision of sample identification beyond traditional barcoding while keeping the costs manageable. While methods for assembly-free sample identification based on genome skims are now available, little is known about how these methods react to the presence of DNA from organisms other than the target species. In this paper, we show that the accuracy of distances computed between a pair of genome skims based on k-mer similarity can degrade dramatically if the skims include contaminant reads; i.e., any reads originating from other organisms. We establish a theoretical model of the impact of contamination. We then suggest and evaluate a solution to the contamination problem: Query reads in a genome skim against an extensive database of possible contaminants (e.g., all microbial organisms) and filter out any read that matches. We evaluate the effectiveness of this strategy when implemented using Kraken-II, in detailed analyses. Our results show substantial improvements in accuracy as a result of filtering but also point to limitations, including a need for relatively close matches in the contaminant database.
The adaptive potential of the middle domain of yeast Hsp90
Authors: Cote-Hammarlof Pamela A. , Fragata Inês , Flynn Julia , Mavor David , Zeldovich Konstantin B. , Bank Claudia , Bolon Daniel N.A. 
Published: November 2019

AbstractThe distribution of fitness effects (DFE) of new mutations across different environments quantifies the potential for adaptation in a given environment and its cost in others. So far, results regarding the cost of adaptation across environments have been mixed, and most studies have sampled random mutations across different genes. Here, we quantify systematically how costs of adaptation vary along a large stretch of protein sequence by studying the DFEs of the same ≈2300 amino-acid changing mutations obtained from deep mutational scanning of 119 amino acids in the middle domain of the heat-shock protein Hsp90 in five environments. This region is known to be important for client binding, stabilization of the Hsp90 dimer, stabilization of the N-terminal-Middle and Middle-C-terminal interdomains, and regulation of ATPase-chaperone activity. Interestingly, we find that fitness correlates well across diverse stressful environments, with the exception of one environment, diamide. Consistent with this result, we find little cost of adaptation; on average only one in seven beneficial mutations is deleterious in another environment. We identify a hotspot of beneficial mutations in a region of the protein that is located within an allosteric center. The identified protein regions that are enriched in beneficial, deleterious, and costly mutations coincide with residues that are involved in the stabilization of Hsp90 interdomains and stabilization of client binding interfaces, or residues that are involved in ATPase chaperone activity of Hsp90. Thus, our study yields information regarding the role and adaptive potential of a protein sequence that complements and extends known structural information.
Simple and low-cost amplifier system for the study of a ventral nerve action potential in earthworm
Authors: Jorquera Orlando 
Published: November 2019

AbstractBasic Biophysics or Neurobiology courses encounter problems when starting their practices due to the complexity and high cost of the equipment. As a consequence, these experiences are replaced by simulation software, leading students to boredom and disinterest, and finally to the lack of understanding of the basic principles of the phenomenon observed. Classical nerve conduction studies for the visualization of action potentials are an example of this, being able to be developed with simple and low-cost amplification circuits, as described in this article. The system showed stability, expected amplification and high signal-to-noise ratio. The action potential of the medial giant fiber (MGF) as lateral giant fiber (LGF) in the ventral nerve cord of the earthwormsLumbricus terrestriswas recorded. The experimental system has met expectations and regains practical, effective and stimulating learning for students.
Gain-of-function genetic screen of the kinome reveals BRSK2 as an inhibitor of the NRF2 transcription factor
Authors: Tamir Tigist Y , Bowman Brittany M , Agajanian Megan J , Goldfarb Dennis , Schrank Travis P , Stohrer Trent , Hale Andrew E , Siesser Priscila F , Weir Seth J , Murphy Ryan M , LaPak Kyle M , Weissman Bernard E , Moorman Nathaniel J , Ben Major M. 
Published: November 2019

AbstractNFE2L2/NRF2 is a transcription factor and master regulator of cellular antioxidant response. Aberrantly high NRF2-dependent transcription is recurrent in human cancer, and conversely NRF2 protein levels as well as activity is diminished with age and in neurodegenerative disorders. Though NRF2 activating drugs are clinically beneficial, NRF2 inhibitors do not yet exist. Here we used a gain-of-function genetic screen of the kinome to identify new druggable regulators of NRF2 signaling. We found that the understudied protein kinase Brain Specific Kinase 2 (BRSK2) and the related BRSK1 kinases suppress NRF2-dependent transcription and NRF2 protein levels in an activity-dependent manner. Integrated phosphoproteomics and RNAseq studies revealed that BRSK2 drives AMPK activation and suppresses mTOR signaling. As a result, BRSK2 kinase activation suppressed ribosome-RNA complexes, global protein synthesis, and NRF2 protein levels. Collectively, our data establish the catalytically active BRSK2 kinase as a negative regulator of NRF2 via the AMPK/mTOR signaling. This signaling axis may prove useful for therapeutically targeting NRF2 in human diseases.Summary StatementBRSK2 suppresses NRF2 signaling by inhibiting protein synthesis through mTOR downregulation.
The expression of YAP1 is increased in high-grade prostatic adenocarcinoma but is reduced in neuroendocrine prostate cancer
Authors: Cheng Siyuan , Prieto-Dominguez Nestor , Yang Shu , Connelly Zachary M. , StPierre Samantha , Rushing Bryce , Watkins Andy , Shi Lawrence , Lakey Meredith , Baiamonte Lyndsey Buckner , Fazili Tajammul , Lurie Aubrey , Corey Eva , Shi Runhua , Yeh Yunshin , Yu Xiuping 
Published: November 2019

ABSTRACTBACKGROUNDAfter long-term androgen deprivation therapy, 25-30% prostate cancer (PCa) acquires an aggressive neuroendocrine (NE) phenotype. Dysregulation of YAP1, a key transcription coactivator of the Hippo pathway, has been related to cancer progression. However, its role in neuroendocrine prostate cancer (NEPC) has not been assessed.METHODSImmunohistochemistry was used to evaluate YAP1 protein levels during PCa initiation and progression. YAP1 knockdown and luciferase reporter assays were used to evaluate the ability of YAP1 to modulate Wnt/beta-Catenin signaling.RESULTSYAP1 expression was present in the basal epithelial cells in benign prostatic tissues, lost in low grade PCa, but elevated in high grade prostate adenocarcinomas. Interestingly, the expression of YAP1 was reduced/lost in both human and mouse NEPC. Finally, YAP1 knockdown in PCa cells activates Wnt/beta-Catenin signaling, which has been implicated in NE differentiation of PCa, supporting a functional involvement of the loss of YAP1 expression in NEPC development.CONCLUSIONSThe expression of YAP1 is elevated in high grade prostate adenocarcinomas while lost in NEPC. Reduced YAP1 activates Wnt/beta-Catenin signaling in PCa cells. These results suggest that when applied to PCa patients, YAP1 inhibitors shall be used with caution.
Genomic Background Governs Opposing Responses to Nalidixic Acid Upon Megaplasmid Acquisition inPseudomonas
Authors: Baltrus David A. , Smith Caitlin , Derrick MacKenzie , Leligdon Courtney , Rosenthal Zoe , Mollico Madison , Moore Andrew , Clark Meara 
Published: November 2019

AbstractHorizontal gene transfer is a significant driver of evolutionary dynamics across microbial populations. Although the benefits of the acquisition of new genetic material are often quite clear, experiments across systems have demonstrated that gene transfer events can cause significant phenotypic changes and entail fitness costs in a way that is dependent on the genomic and environmental context. Here we test for the generality of one previously identified cost, sensitization of cells to the antibiotic nalidixic acid after acquisition of a ∼1Mb megaplasmid, across Pseudomonas strains and species. Overall, we find that the presence of this megaplasmid sensitizes many different Pseudomonas strains to nalidixic acid, but that this same horizontal gene transfer event increases resistance ofPseudomonas putidaKT2440 to nalidixic acid across assays as well as to ciprofloxacin under competitive conditions. These phenotypic results are not easily explained away as secondary consequences of overall fitness effects and appear to occur independently of another cost associated with this megaplasmid, sensitization to higher temperatures. Lastly, we draw parallels between these reported results and the phenomenon of sign epistasis forde novomutations and explore how context dependence of effects of plasmid acquisition could impact overall evolutionary dynamics and the evolution of antimicrobial resistance.ImportanceNumerous studies have demonstrated that gene transfer events (e.g. plasmid acquisition) can entail a variety of costs that arise as byproducts of the incorporation of foreign DNA into established physiological and genetic systems. These costs can be ameliorated through evolutionary time by the occurrence of compensatory mutations, which stabilize presence of a horizontally transferred region within the genome but which also may skew future adaptive possibilities for these lineages. Here we demonstrate another possible outcome, that phenotypic changes arising as a consequence of the same horizontal gene transfer event are costly to some strains but may actually be beneficial in other genomic backgrounds under the right conditions. These results provide new a new viewpoint for considering conditions that promote plasmid maintenance and highlight the influence of genomic and environmental contexts when considering amelioration of fitness costs after HGT events.
Pseudohyphal growth of the emerging pathogenCandida aurisis triggered by genotoxic stress through the S phase checkpoint
Authors: Bravo Ruiz Gustavo , Ross Zoe K. , Gow Neil A.R. , Lorenz Alexander 
Published: November 2019

ABSTRACTThe morphogenetic switching between yeast cells and filaments (true hyphae and pseudohyphae) is a key cellular feature required for full virulence in many polymorphic fungal pathogens, such asCandida albicans. In the recently emerged yeast pathogenCandida auris, occasional elongation of cells has been reported. However, environmental conditions and genetic triggers for filament formation have remained elusive. Here, we report that induction of DNA damage and perturbation of replication forks by treatment with genotoxins, such as hydroxyurea, methyl methanesulfonate, and the clinically relevant fungistatic 5-fluorocytosine, causes filamentation inC. auris. The filaments formed were characteristic of pseudohyphae and not parallel-sided true hyphae. Pseudohyphal growth is apparently signalled through the S phase checkpoint and, interestingly, is Tup1-independent inC. auris. Intriguingly, the morphogenetic switching capability is strain-specific inC. auris, highlighting the heterogenous nature of the species as a whole.IMPORTANCECandida aurisis a newly emerged fungal pathogen of humans. This species was first reported in 2009, when it was identified in an ear infection of a patient in Japan. However, despite intense interest in this organism as an often multidrug-resistant fungus there is little knowledge about its cellular biology. During infection of human patients, fungi are able to change cell shape from ellipsoidal yeast cells to elongated filaments to adapt to various conditions within the host organism. There are different types of filaments, which are triggered by reactions to different cues.Candida aurisfails to form filaments when exposed to triggers that stimulate yeast-filament morphogenesis in other fungi. Here, we show that it does form filaments when its DNA is damaged. These conditions might arise whenCandida auriscells interact with host immune cells, or growing in certain host tissues (kidney, bladder), or during treatment with antifungal drugs.