bluuebunny/crossref_metadata_2025_split huggingface dataset:
Personalized anti-cancer drug combination prediction by an Integrated Multi-level Network
Authors: Feng Fangyoumin , Zhang Zhengtao , Ding Guohui , Hui Lijian , Li Yixue , Li Hong 
Published: May 2020

AbstractAnti-cancer drug combination is an effective solution to improve treatment efficacy and overcome resistance. Here we propose a network-based method (DComboNet) to prioritize the candidate drug combinations. The level one model is to predict generalized anti-cancer drug combination effectiveness and level two model is to predict personalized drug combinations. By integrating drugs, genes, pathways and their associations, DComboNet achieves better performance than previous methods, with high AUC value of around 0.8. The level two model performs better than level one model by introducing cancer sample specific transcriptome data into network construction. DComboNet is further applied on finding combinable drugs for sorafenib in hepatocellular cancer, and the results are verified with literatures and cell line experiments. More importantly, three potential mechanism modes of combinations were inferred based on network analysis. In summary, DComboNet is valuable for prioritizing drug combination and the network model may facilitate the understanding of the combination mechanisms.
Resolution of subcomponents of synaptic release from post-synaptic currents in rat hair-cell/auditory-nerve fiber synapses
Authors: Young Eric D. , Wu Jingjing Sherry , Niwa Mamiko , Glowatzki Elisabeth 
Published: May 2020

AbstractThe synapse between inner hair cells and auditory nerve fiber dendrites shows large EPSCs, which are either monophasic or multiphasic. Multiquantal or uniquantal flickering release have been proposed to underlie the unusual multiphasic waveforms. Here the nature of multiphasic waveforms is analyzed using EPSCs recordedin vitroin rat afferent dendrites. Spontaneous EPSCs were deconvolved into a sum of presumed release events with monophasic EPSC waveforms. Results include: first, the charge of EPSCs is about the same for multiphasic versus monophasic EPSCs. Second, EPSC amplitudes decline with the number of release events per EPSC. Third, there is no evidence of a mini-EPSC. Most results can be accounted for by versions of either uniquantal or multiquantal release. However, serial neurotransmitter release in multiphasic EPSCs shows properties that are not fully explained by either model, especially that the amplitudes of individual release events is established at the beginning of a multiphasic EPSC, constraining possible models of vesicle release.
The Evolution and Fate of Diversity Under Hard and Soft Selection
Authors: Chen Patrick J. , Kassen Rees 
Published: May 2020

AbstractHow genetic variation arises and persists over evolutionary time despite the depleting effects of natural selection remains a long-standing question. Here, we investigate the impacts of two extreme forms of population regulation – at the level of the total, mixed population (hard selection) and at the level of local, spatially distinct patches (soft selection) – on the emergence and fate of diversity under strong divergent selection. We find that while the form of population regulation has little effect on rates of diversification it can modulate the long-term fate of genetic variation, diversity being more readily maintained under soft selection compared to hard selection. The mechanism responsible for coexistence is negative frequency dependent selection which, while present initially under both forms of population regulation, persists over the long-term only under soft selection. Importantly, coexistence is robust to continued evolution of niche specialist types under soft selection but not hard selection. These results suggest that soft selection could be a general mechanism for the maintenance of ecological diversity over evolutionary time scales.
Contrast-FEL – a test for differences in selective pressures at individual sites among clades and sets of branches
Authors: Kosakovsky Pond Sergei L. , Wisotsky Sadie R , Escalante Ananias , Magalis Brittany Rife , Weaver Steven 
Published: May 2020

AbstractA number of evolutionary hypotheses can be tested by comparing selective pressures among sets of branches in a phylogenetic tree. When the question of interest is to identify specific sites within genes that may be evolving differently, a common approach is to perform separate analyses on subsets of sequences, and compare parameter estimates in apost hocfashion. This approach is statistically suboptimal, and not always applicable. Here, we develop a simple extension of a popular fixed effects likelihood method in the context of codon-based evolutionary phylogenetic maximum likelihood testing, Contrast-FEL. It is suitable for identifying individual alignment sites where any among theK ≥2 sets of branches in a phylogenetic tree have detectably differentdN/dSratios, indicative of different selective regimes. Using extensive simulations, we show that Contrast-FEL delivers good power, exceeding 90% for sufficiently large differences, while maintaining tight control over false positive rates. We conclude by applying Contrast-FEL to data from five previously published studies spanning a diverse range of organisms and focusing on different evolutionary questions.
Predation Has Small, Short-Term, and in Certain Conditions Random Effect on the Evolution of Aging
Authors: Lenart Peter , Bienertová-Vašků Julie , Berec Luděk 
Published: May 2020

AbstractThe pace of aging varies considerably in nature. Historically, scientists focused mostly on why and how has aging evolved, while only a few studies explored mechanisms driving evolution of specific rates of aging. Here we develop an agent-based model simulating evolution of aging in prey subject to predation. Our results suggest that predation affects the pace of aging in prey only if young, vivid animals are not much more likely to escape predators than the old ones. However, even this effect slowly vanishes when the predator diet composition evolves, too. Furthermore, evolution of a specific aging rate, in our model, is driven mainly by a single parameter, the strength of a trade-off between aging and fecundity. Indeed, in absence of this trade-off the evolutionary impacts of predation on the prey aging rate appear random. Our model produces several testable predictions which may be useful for other areas of aging research.
Novel ACE2-Independent Carbohydrate-Binding of SARS-CoV-2 Spike Protein to Host Lectins and Lung Microbiota
Authors: Chiodo Fabrizio , Bruijns Sven C.M. , Rodriguez Ernesto , Li R.J. Eveline , Molinaro Antonio , Silipo Alba , Di Lorenzo Flaviana , Garcia-Rivera Dagmar , Valdes-Balbin Yury , Verez-Bencomo Vicente , van Kooyk Yvette 
Published: May 2020

AbstractThe immediate call for translational research in the field of coronavirus disease (COVID-19) pandemic, needs new and unexplored angles to support and contribute to this important worldwide health problem. The aim of this study is to better understand the pathogenic mechanisms underlying COVID-19, deciphering the carbohydrate-mediated interactions of the SARS-CoV-2 spike protein. We studied the carbohydrate-binding receptors that could be important for viral entry and for immune-modulatory responses, and we studied the interactions of the spike protein with the host lung microbiota. Exploring solid-phase immunoassays, we evaluated the interactions between the SARS-CoV-2 spike protein and a library of 12 different human carbohydrate-binding proteins (C-type lectins and Siglecs) involved in binding, triggering and modulation of innate and adaptive immune-responses. We revealed a specific binding of the SARS-CoV-2 spike protein to the receptors DC-SIGN, MGL, Siglec-9 and Siglec-10 that are all expressed on myeloid immune cells. In addition, because the lung microbiota can promote or modulate viral infection, we studied the interactions between the SARS-CoV-2 spike protein and a library ofStreptococcus pneumoniaecapsular polysaccharides, as well as other bacterial glyco-conjugates. We show specific binding of the spike protein to differentS. pneumoniaecapsular polysaccharides (serotypes 19F and 23F but not to serotype 14). Moreover we demonstrated a specific binding of SARS-CoV-2 spike protein to the lipopolysaccharide from the opportunistic human pathogenPseudomonas aeruginosa, one of the leading cause of acute nosocomial infections and pneumonia. Interestingly, we identified rhamnosylated epitopes as one of the discriminating structures in lung microbiota to bind SARS-CoV-2 spike protein. In conclusion, we revealed novel ACE2-independent carbohydrate-mediated interactions with immune modulating lectins expressed on myeloid cells, as well as host lung microbiota glyco-conjugates. Our results identified new molecular pathways using host lectins and signalling, that may contribute to viral infection and subsequent immune exacerbation. Moreover we identified specific rhamnosylated epitopes in lung microbiota to bind SARS-CoV-2, providing a hypothetical link between the presence of specific lung microbiota and SARS-CoV-2 infection and severity.
Novel method for the prediction of drug-drug Interaction based on Gene Expression profiles
Authors: Taguchi Yh. , Turki Turki 
Published: May 2020

ABSTRACTThe accurate prediction of new interactions between drugs is important for avoiding unknown (mild or severe) adverse reactions to drug combinations. The development of effectivein silicomethods for evaluating drug interactions based on gene expression data requires an understanding of how various drugs alter gene expression. Current computational methods for the prediction of drug-drug interactions (DDIs) utilize data for known DDIs to predict unknown interactions. However, these methods are limited in the absence of known predictive DDIs. To improve DDIs’ interpretation, a recent study has demonstrated strong non-linear (i.e., dosedependent) effects of DDIs. In this study, we present a new unsupervised learning approach involving tensor decomposition (TD)-based unsupervised feature extraction (FE) in 3D. We utilize our approach to reanalyze available gene expression profiles forSaccharomyces cerevisiae. We found that non-linearity is possible, even for single drugs. Thus, non-linear dose-dependence cannot always be attributed to DDIs. Our analysis provides a basis for the design of effective methods for evaluating DDIs.
Shifts from pulled to pushed range expansions caused by reduction of landscape connectivity
Authors: Dahirel Maxime , Bertin Aline , Haond Marjorie , Blin Aurélie , Lombaert Eric , Calcagno Vincent , Fellous Simon , Mailleret Ludovic , Malausa Thibaut , Vercken Elodie 
Published: May 2020

AbstractRange expansions are key processes shaping the distribution of species; their ecological and evolutionary dynamics have become especially relevant today, as human influence reshapes ecosystems worldwide. Many attempts to explain and predict range expansions assume, explicitly or implicitly, so-called “pulled” expansion dynamics, in which the low-density edge populations provide most of the “fuel” for the species advance. Some expansions, however, exhibit very different dynamics, with high-density populations behind the front “pushing” the expansion forward. These two types of expansions are predicted to have different effects on e.g. genetic diversity and habitat quality sensitivity. However, empirical studies are lacking due to the challenge of generating reliably pushed vs. pulled expansions in the laboratory, or discriminating them in the field. We here propose that manipulating the degree of connectivity among populations may prove a more generalizable way to create pushed expansions. We demonstrate this with individual-based simulations as well as replicated experimental range expansions (using the parasitoid waspTrichogramma brassicaeas model). By analyzing expansion velocities and neutral genetic diversity, we showed that reducing connectivity led to pushed dynamics. Low connectivity alone, i.e. without density-dependent dispersal, can only lead to “weakly pushed” expansions, where invasion speed conforms to pushed expectations, but the decline in genetic diversity does not. In empirical expansions however, low connectivity may in some cases also lead to adjustments to the dispersal-density function, recreating “classical” pushed expansions. In the current context of habitat loss and fragmentation, we need to better account for this relationship between connectivity and expansion regimes to successfully predict the ecological and evolutionary consequences of range expansions.
A framework for designing miRNA-based distributed cell classifier circuits
Authors: Nowicka Melania , Siebert Heike 
Published: May 2020

AbstractMotivationCell classifiers are synthetic bio-devices performing type-specificin vivoclassification. The circuits identify a cell state based on its molecular fingerprint. In particular, the classifiers may be designed to recognize cancerous cells and trigger their apoptosis, shaping a novel therapy for cancer patients. Recently, we introduced a new theoretical design of such devices employing distributed classifiers. Here, a group of single-circuit classifiers decides collectively according to a pre-defined threshold function whether a cell is cancerous. The multi-circuit architecture has shown the potential to predict the cell condition with high accuracy. However, lack of far-reaching machinery to design and evaluate distributed cell classifiers, in particular, assessing their robustness to noise and novel information, makes their application limited.ResultsIn this study, we present a comprehensive framework for designing and evaluating miRNA-based distributed cell classifiers comprising data simulation, pre-processing, and an extensive testing scheme. We develop optimization criteria that allow increasing the accuracy and robustness of classifiers to noise and novel information as shown in simulated and real-world data studies. The evaluation performed on cancer data demonstrates that distributed classifiers outperform single-circuit designs in terms of prediction accuracy. Our classifiers include relevant miRNAs previously described in the literature, as well as more complex regulation patterns included in the data.AvailabilityThe code and data are available at:https://github.com/MelaniaNowicka/RAccoon.Contactm.nowicka@fu-berlin.de
RBFOX2 is Critical for Maintaining Alternative Polyadenylation Patterns and Mitochondrial Health in Rat Myoblasts
Authors: Cao Jun , Verma Sunil K. , Jaworski Elizabeth , Mohan Stephanie , Nagasawa Chloe K. , Rayavara Kempaiah , Sooter Amanda , Miller Sierra N. , Holcomb Richard J. , Ji Ping , Elrod Nathan D. , Yildirim Eda , Wagner Eric J. , Popov Vsevolod , Garg Nisha J. , Routh Andrew L. , Kuyumcu-Martinez Muge N. 
Published: May 2020

SUMMARYRBFOX2, which has a well-established role in alternative splicing, is linked to heart diseases. However, it is unclear whether RBFOX2 has other roles in RNA processing that can influence gene expression/function in muscle cells, contributing to disease pathology. Here, we employed both 3’-end and nanopore cDNA sequencing to reveal a previously unrecognized role for RBFOX2 in maintaining alternative polyadenylation (APA) signatures in myoblasts. We found that RBFOX2-mediated APA modulates both mRNA levels and isoform expression of a collection of genes including contractile and mitochondrial genes. We identified the key muscle-specific contractile gene,Tropomyosin 1and essential mitochondrial gene,Slc25a4as APA targets of RBFOX2. Unexpectedly, depletion of RBFOX2 adversely affected mitochondrial health in myoblasts that is in part mediated by disrupted APA of mitochondrial geneSlc25a4. Mechanistically, we found that RBFOX2 regulation ofSlc25a4APA is mediated through consensus RBFOX2 binding motifs near the distal polyadenylation site enforcing the use of the proximal polyadenylation site. In sum, our results unveiled a new role for RBFOX2 in fine tuning expression levels of mitochondrial and contractile genes via APA in myoblasts relevant to heart diseases.
CCR4-NOT complex nuclease Caf1 is a novel shuttle factor involved in the degradation of ubiquitin-modified proteins by 26S proteasome
Authors: Kandasamy Ganapathi , Pradhan Ashis Kumar , Palanimurugan R 
Published: May 2020

AbstractProtein degradation by ubiquitin proteasome system (UPS) is the major selective proteolytic pathway responsible for the degradation of short lived proteins ranging from regulatory proteins to abnormal proteins. Many diseases are associated with abnormal protein degradation; occasionally such dysregulated protein degradation is compensated by various transcriptional and translational control mechanisms in the cell. Among those pathways CCR4-NOT protein complex is responsible for transcriptional and transitional control of various gene expressions. Furthermore, CCR4-NOT complex also has a RING type ubiquitin ligase (E3) which is required for the degradation of several proteins. Here we report a novel function that the CCR4-NOT complex 3’-5’ exonuclease Caf1 is involved in ubiquitindependent degradation of short lived proteins by the 26S proteasome in yeastSaccharomyces cerevisiae. caf1deletion results in stabilization of R-Ura3 (N-end rule) and Ub-V76-Ura3 (Ubiquitin fusion degradation) substrates from proteasomal degradation. Additionally,caf1deletion accumulates ubiquitin-modified Ub-V76-Ura3 proteins and Caf1 binds to poly-ubiquitin conjugates and linear tetra ubiquitin chains. Surprisingly, Caf1 interacts with 19S regulatory particle complex of the 26S proteasome. Therefore, we conclude that Caf1 has an exciting novel function as an ubiquitin shuttle factor in which Caf1 targets ubiquitin-modified proteins to 26S proteasome for efficient degradation.
BLM-dependent Break-Induced Replication handles DSBs in transcribed chromatin upon impaired RNA:DNA hybrids dissolution
Authors: Cohen S , Guenolé A , Marnef A , Clouaire T , Puget N , Rocher V , Arnould C , Aguirrebengoa M , Genais M , Vernekar D , Mourad R , Borde V , Legube G 
Published: May 2020

AbstractTranscriptionally active loci are particularly prone to breakage and mounting evidence suggest that DNA Double-Strand Breaks arising in genes are handled by a dedicated repair pathway, Transcription-Coupled DSB Repair (TC-DSBR), that entails R-loops accumulation and dissolution. Here, we uncovered a critical function of the Bloom RecQ DNA helicase (BLM) in TC-DSBR in human cells. BLM is recruited in a transcription dependent-manner at DSBs where it fosters resection, RAD51 binding and accurate Homologous Recombination repair. However, in a R-loop dissolution-deficient background BLM switches from promoting Homologous Recombination to promoting Break-Induced Replication (BIR), which strongly impairs cell viability. Altogether our work unveils a role for BLM in BIR at DSBs in active chromatin, and highlights the toxic potential of RNA:DNA hybrids that accumulate at these transcription-associated DSBs.
Purification of recombinant α-Synuclein: a comparison of commonly used protocols
Authors: Stephens Amberley D. , Matak-Vinkovic Dijana , Schierle Gabriele S. Kaminski 
Published: May 2020

AbstractThe insoluble aggregated form of the protein alpha-synuclein (aSyn) is associated with synucleinopathies, such as Parkinson’s Disease, therefore great effort is put into understanding why and how this initially soluble protein misfolds. The initial state of aSyn, e.g. presence of contaminants, adducts, oligomers or degradation products, can greatly influence the outcome of an assay, such as determining its aggregation kinetics. Here, we compare four commonly used protocols for the isolation of recombinant aSyn fromE. coliby boiling, acid precipitation, ammonium sulphate precipitation and periplasmic lysis followed by ion exchange chromatography and gel filtration. We identified, using non-denaturing electrospray ionisation mass spectrometry of the differently extracted aSyn samples, that aSyn isolated by acid precipitation and periplasmic lysis yielded the highest percentage of monomer, 100% and 96.5% respectively. aSyn purity was again highest in samples isolated by acid precipitation and periplasmic lysis, yet aggregation assays displayed differences in the aggregation rate of aSyn isolated by all four methods.HighlightsA rapid protocol; expression day one, two step purification day two.The periplasmic lysis-based protocol yielded 95% pure aSyn.Acid precipitation and periplasmic lysis-based protocols yielded the highest proportion of monomeric aSyn at 100% and 96.5%, respectively.
A kinetic model of the central carbon metabolism for acrylic acid production inEscherichia coli
Authors: Oliveira Alexandre , Rodrigues Joana , Ferreira Eugénio , Rodrigues Lígia , Dias Oscar 
Published: May 2020

AbstractAcrylic acid is a value-added chemical used in industry to produce diapers, coatings, paints, and adhesives, among many others. Due to its economic importance, there is currently a need for new and sustainable ways to synthesise it. Recently, the focus has been laid in the use ofEscherichia colito express the full bio-based pathway using 3-hydroxypropionate as an intermediary through three distinct pathways (glycerol, malonyl-CoA, andβ-alanine). Hence, the goals of this work were to use COPASI software to assess which of the three pathways has a higher potential for industrial-scale production, from either glucose or glycerol, and identify potential targets to improve the biosynthetic pathways yields.When compared to the available literature, the models developed during this work successfully predict the production of 3-hydroxypropionate, using glycerol as carbon source in the glycerol pathway, and using glucose as a carbon source in the malonyl-CoA andβ-alanine pathways. Finally, this work allowed to identify four potential over-expression targets (glycerol-3-phosphate dehydrogenase (G3pD), acetyl-CoA carboxylase (AccC), aspartate aminotransferase (AspAT), and aspartate carboxylase (AspC)) that should, theoretically, result in higher AA yields.Author summaryAcrylic acid is an economically important chemical compound due to its high market value. Nevertheless, the majority of acrylic acid consumed worldwide its produced from petroleum derivatives by a purely chemical process, which is not only expensive, but it also contributes towards environment deterioration. Hence, justifying the current need for sustainable novel production methods that allow higher profit margins. Ideally, to minimise production cust, the pathway should consist in the direct bio-based production from microbial feedstocks, such as Escherichia coli, but the current yields achieved are still to low to compete with conventional method. In this work, even though the glycerol pathway presented higher yields, we identified the malonyl-CoA route, when using glucose as carbon source, as having the most potential for industrial-scale production, since it is cheaper to implement. Furthermore, we also identified potential optimisation targets for all the tested pathways, that can help the bio-based method to compete with the conventional process.