bluuebunny/crossref_metadata_2025_split huggingface dataset:
Selfish mitochondria exploit nutrient status across different levels of selection
Authors: Gitschlag Bryan L. , Tate Ann T. , Patel Maulik R. 
Published: February 2020

AbstractCooperation and cheating are widespread evolutionary strategies. Competition can simultaneously favor cheating within groups and cooperation between groups. Selfish or cheater mitochondrial DNA (mtDNA) mutants proliferate within hosts while being selected against at the level of host fitness. How does environment govern competition between cooperators and cheaters across different selection levels? Focusing on food availability, we address this question using heteroplasmicCaenorhabditis elegans. We show that by promoting germline development, nutrient status provides the niche space for mtDNA variants to compete. However, the within-host advantage of selfish mtDNA requires additional conditions, namely the FoxO transcription factor DAF-16. During food scarcity, DAF-16 mitigates the host fitness cost of the selfish mtDNA. We conclude that food availability, and resilience to food scarcity, govern selfish mtDNA dynamics across the levels of selection. Our study integrates an evolutionary framework with experimentation to identify cellular mechanisms underlying the multilevel selection that characterizes cheater dynamics.
Directed assembly and concentrating of micro/nanoparticles, cells, and vesicles via low-power near-infrared laser generated plasmonic microbubbles
Authors: Ohannesian Nareg , Li Jingting , Misbah Ibrahim , Zhao Fusheng , Shih Wei-Chuan 
Published: February 2020

AbstractDirected assembly and concentrating of micro- and nanoparticles via laser generated plasmonic microbubbles in a liquid environment is an emerging technology. For effective heating, visible light has been primarily employed in existing demonstrations. In this paper, we demonstrate a new plasmonic platform based on nanoporous gold disk (NPGD) array. Thanks to the highly tunable localized surface plasmon resonance of the NPGD array, microbubble of controlled size can be generated by near-infrared (NIR) light. Using NIR light provides several key advantages over visible light in less interference with standard microscopy and fluorescence imaging, preventing fluorescence photobleaching, less susceptible to absorption and scattering in turbid biological media, and much reduced photochemistry, phototoxicity and whatsoever. The large surface-to-volume ratio of NPGD further facilitates the heat transfer from these gold nanoheaters to the surroundings, achieving unprecedented low-power operation. While the microbubble is formed, the surrounding liquid circulates and direct microparticles randomly dispersed in the liquid to the bottom NPGD surface, yielding unique assemblies of microstructures. Such capability can also be employed in concentrating suspended colloidal nanoparticles at desirable sites and with preferred configuration, both enhancing the sensor performance. In addition to various micro- and nanoparticles, the plasmonic microbubbles are also shown to collect biological cells and nanovesicles. By using a spatial light modulator (SLM) to project the laser in arbitrary patterns, parallel assembly can be achieved to fabricate an array of clusters. These assemblies have been characterized using optical microscopy, scanning electron microscope, hyperspectral localized surface plasmon resonance imaging and hyperspectral Raman imaging.
Genome-wide investigation of gene-cancer associations for the prediction of novel therapeutic targets in oncology
Authors: Bazaga Adrián , Leggate Dan , Weisser Hendrik 
Published: February 2020

ABSTRACTA major cause of failed drug discovery programs is suboptimal target selection, resulting in the development of drug candidates that are potent inhibitors, but ineffective at treating the disease. In the genomics era, the availability of large biomedical datasets with genome-wide readouts has the potential to transform target selection and validation. In this study we investigate how computational intelligence methods can be applied to predict novel therapeutic targets in oncology. We compared different machine learning classifiers applied to the task of drug target classification for nine different human cancer types. For each cancer type, a set of “known” target genes was obtained and equally-sized sets of “non-targets” were sampled multiple times from the human protein-coding genes. Models were trained on mutation, gene expression (TCGA), and gene essentiality (DepMap) data. In addition, we generated a numerical embedding of the interaction network of protein-coding genes using deep network representation learning and included the results in the modeling. We assessed feature importance using a random forests classifier and performed feature selection based on measuring permutation importance against a null distribution. Our best models achieved good generalization performance based on the AUROC metric. With the best model for each cancer type, we ran predictions on more than 15,000 protein-coding genes to identify potential novel targets. Our results indicate that this approach may be useful to inform early stages of the drug discovery pipeline.
Preliminary Evidence of the role of estrogen and tamoxifen-induced regulation of complement proteins in rat hippocampus
Authors: Kumar Pavan , Dhar Pushpa 
Published: February 2020

AbstractEffects of Estrogen (E2) is widespread in the human body; still, an unresolved paradox. Neurodegeneration and neuroinflammation are inherently associated with age progression, debilitating by hormone deprivation, especially in female. Senescent cells accumulate with age and promote tissue deterioration in the body system. Neurodegenerative diseases drive a healthy life towards to morbidity and feebleness; despite the different etiology, uncontrolled inflammation is one of the significant causals factors. We here used post-menopausal model (ovariectomized female rat), E2 replenishment therapy reduces the expression of inflammatory mediators, such as complement proteins (C3, C1q, and C3aR) in these animals.E2 therapy could limit the ovariectomy-induced increase of inflammatory events in brain regions such as the hippocampus. Also, the duration of hormone deprivation could be a determinant for the intensity of the anti-inflammatory actions of estrogen. On the whole, considerable evidence, including that from the present study supports the view that complement biosynthesis, which plays a significant role in phagocytosis of cellular debris and synaptic pruning of postnatal neural circuits goes uncontrolled and could be the inducing factor for enhanced neurodegeneration following hormone deprivation.
TOR coordinates nucleotide availability with ribosome biogenesis in plants
Authors: Busche Michael , Scarpin M. Regina , Hnasko Robert , Brunkard Jacob O. 
Published: February 2020

ABSTRACTTARGET OF RAPAMYCIN (TOR) is a conserved eukaryotic Ser/Thr protein kinase that coordinates growth and metabolism with nutrient availability. We conducted a medium-throughput functional genetic screen to discover essential genes that promote TOR activity in plants, and identified a critical regulatory enzyme, cytosolic phosphoribosyl pyrophosphate (PRPP) synthetase (PRS4). PRS4 synthesizes cytosolic PRPP, a key upstream metabolite in nucleotide synthesis and salvage pathways. We found thatprs4knockouts are embryo-lethal inA. thaliana, and that silencingPRS4expression inN. benthamianacauses pleiotropic developmental phenotypes, including dwarfism, aberrant leaf shape, and delayed flowering. Transcriptomic analysis revealed that ribosome biogenesis is among the most strongly repressed processes inprs4knockdowns. Building on these results, we discovered that TOR activity is inhibited by chemical or genetic disruption of nucleotide biosynthesis, but that this effect can be reversed by supplying plants with physiological levels of nucleotides. Finally, we show that TOR transcriptionally promotes nucleotide biosynthesis to support the demands of ribosomal RNA synthesis. We propose that TOR coordinates ribosome biogenesis with nucleotide availability in plants to maintain metabolic homeostasis and support growth.
Genetic Analyses of Blood Cell Structure for Biological and Pharmacological Inference
Authors: Akbari Parsa , Vuckovic Dragana , Jiang Tao , Kundu Kousik , Kreuzhuber Roman , Bao Erik L. , Mayer Louisa , Collins Janine H. , Downes Kate , Georges Michel , Grassi Luigi , Guerrero Jose A. , Kaptoge Stephen , Knight Julian C. , Meacham Stuart , Sambrook Jennifer , Seyres Denis , Stegle Oliver , Verboon Jeffrey M. , Walter Klaudia , Watkins Nicholas A. , Danesh John , Roberts David J. , Di Angelantonio Emanuele , Sankaran Vijay G. , Frontini Mattia , Burgess Stephen , Kuijpers Taco , Peters James E. , Butterworth Adam S. , Ouwehand Willem H. , Soranzo Nicole , Astle William J. 
Published: February 2020

SUMMARYThousands of genetic associations with phenotypes of blood cells are known, but few are with phenotypes relevant to cell function. We performed GWAS of 63 flow-cytometry phenotypes, including measures of cell granularity, nucleic acid content, and reactivity, in 39,656 participants in the INTERVAL study, identifying 2,172 variant-trait associations. These include associations mediated by functional cellular structures such as secretory granules, implicated in vascular, thrombotic, inflammatory and neoplastic diseases. By integrating our results with epigenetic data and with signals from molecular abundance/disease GWAS, we infer the hematopoietic origins of population phenotypic variation and identify the transcription factor FOG2 as a regulator of plateletα-granularity. We show how flow cytometry genetics can suggest cell types mediating complex disease risk and suggest efficacious drug targets, presenting Daclizumab/Vedolizumab in autoimmune disease as positive controls. Finally, we add to existing evidence supporting IL7/IL7-R as drug targets for multiple sclerosis.
A High-Throughput Gravimetric Phenotyping Platform for Real-Time Physiological Screening of Plant–Environment Dynamic Responses
Authors: Dalal Ahan , Shenhar Itamar , Bourstein Ronny , Mayo Amir , Grunwald Yael , Averbuch Nir , Attia Ziv , Wallach Rony , Moshelion Menachem 
Published: February 2020

ABSTRACTFood security for the growing global population is a major concern. The data provided by genomic tools far exceeds the supply of phenotypic data, creating a knowledge gap. To meet the challenge of improving crops to feed the growing global population, this gap must be bridged.Physiological traits are considered key functional traits in the context of responsiveness or sensitivity to environmental conditions. Many recently introduced high-throughput phenotyping techniques are based on remote sensing or imaging and are capable of directly measuring morphological traits, but measure physiological parameters only indirectly.This paper describes a method for direct physiological phenotyping that has several advantages for the functional phenotyping of plant–environment interactions. It aims to help users overcome the many challenges encountered in the use of load-cell gravimetric systems and pot experiments. The suggested techniques will enable users to distinguish between soil weight, plant weight and soil water content, providing a method for continuous and simultaneous measurement of dynamic soil, plant and atmosphere conditions, alongside key physiological traits. This method allows researchers to closely mimic field stress scenarios while taking into consideration the environment’s effect on the plant’s physiology. This method also minimizes pot effects, which are one of the major problems in pre-field phenotyping. It includes a feedback fertigation system that enables a truly randomized experimental design with a field-like plant density. This system detects the soil-water content limiting threshold (θ) and allows for the translation of data into knowledge through the use of a real-time analytic tool and an online statistical resource. This method for the rapid and direct measurement of the physiological responses of multiple plants to a dynamic environment has great potential for use in screening for beneficial traits associated with responses to abiotic stress, in the context of pre-field breeding and crop improvement.SUMMARYThis high-throughput, whole-plant water relations gravimetric phenotyping method enables direct and simultaneous real-time measurements and analysis of multiple yield-related physiological traits involved in dynamic plant–environment interactions.
Machine learning reveals heterogeneous responses to FAK, Rac, Rho, and Cdc42 inhibition on vascular smooth muscle cell spheroid formation and morphology
Authors: Vaidyanathan Kalyanaraman , Wang Chuangqi , Krajnik Amanda , Yu Yudong , Choi Moses , Lin Bolun , Heo Su-Jin , Kolega John , Lee Kwonmoo , Bae Yongho 
Published: February 2020

SUMMARYAtherosclerosis and vascular injury are characterized by neointima formation caused by the aberrant accumulation and proliferation of vascular smooth muscle cells (VSMCs) within the vessel wall. Understanding how to control VSMCs would advance the effort to treat vascular disease. However, the response to treatments aimed at VSMCs is often different among patients with the same disease condition, suggesting patient-specific heterogeneity in VSMCs. Here, we present an experimental and computational method called HETEROID (Heterogeneous Spheroid), which examines the heterogeneity of the responses to drug treatments at the single-spheroid level by combining a VSMC spheroid model and machine learning (ML) analysis. First, we established a VSMC spheroid model that mimics neointima formation induced by atherosclerosis and vascular injury. We found that FAK-Rac/Rho, but not Cdc42, pathways regulate the VSMC spheroid formation through N-cadherin. Then, to identify the morphological subpopulations of drug-perturbed spheroids, we used an ML framework that combines deep learning-based spheroid segmentation and morphological clustering analysis. Our ML approach reveals that FAK, Rac, Rho, and Cdc42 inhibitors differentially affect the spheroid morphology, suggesting there exist multiple distinct pathways governing VSMC spheroid formation. Overall, our HETEROID pipeline enables detailed quantitative characterization of morphological changes in neointima formation, that occurs in vivo, by single-spheroid analysis of various drug treatments.
Beliefs and attitudes towards child epilepsy: A structural equation model
Authors: Silva Luanna G. , Beltrão Izabel C. S. L. , Bandeira Paulo F. R. , Delmondes Gyllyandeson A. , Alencar Cicero D. , Damasceno Simone S. , Kerntopf Marta R. 
Published: February 2020

ABSTRACTInfantile epilepsy is a chronic neurological disease permeated by negative beliefs and attitudes that strengthen social stigma and discrimination, as well as profoundly limit the routine of the affected child. Therefore, the objective of this study was to analyze the possible influencing factors of the beliefs and attitudes towards childhood epilepsy among users of the Family Health Strategy. 300 subjects participated. Variable associations were significant (p<0.05) between religions with positive beliefs and attitudes in the neurological dimension (β: 1.040; p: 0.044); an increase in educational level had a significant relationship with negative beliefs and attitudes in the environmental/psychophysical dimension (β: −0.723; p: 0.040); having a child was significant for negative beliefs and attitudes in the environmental/psychophysical dimension (β: 1.120; p: 0.043) and for positive beliefs in the metaphysical dimension (β: −0,244; p: 0.028). This research contributed to the identification of factors influencing beliefs and attitudes towards childhood epilepsy existing in the studied Brazilian cultural context with the aim of contributing to a better implementation of actions directed to education in epilepsy.
Mate sharing in male stump-tailed macaques as a possible case of coalition-like behavior to modify the group-wise fitness distribution
Authors: Toyoda Aru , Maruhashi Tamaki , Malaivijitnond Suchinda , Koda Hiroki , Ihara Yasuo 
Published: February 2020

ABSTRACTIn multi-male multi-female groups of animals, male reproductive success is often skewed toward top-ranking males. Coalition formation by middle- to low-rankers can be seen as a collaborative effort to modify the distribution of reproductive success within the group, so that they gain more than they would do otherwise. It has been pointed out, on the other hand, that a coalition of top-ranking males could hardly be profitable in the sense that they would gain little additional benefit from making collaborative effort. Here we report our novel observation of facultative sharing of mating opportunities among males in a wild population of stump-tailed macaques (Macaca arctoides) as a possible case of coalition-like behavior in which dominant males jointly guard females from mating with subordinate males and actively share mating opportunities within the allies. First, we report our novel observation of facultative sharing of mating opportunities in male stump-tailed macaques, where two or more males remain in close proximity to and copulate with a female in turn without contesting or sneaking. Second, considering the kind of coalition formation in which dominant males collaboratively exclude subordinates from mating competition and thereby strengthen the reproductive skew that already exists, we specify, by means of mathematical modeling, the condition for this kind of coalition formation to be selectively favored. Finally, we derive predictions about the occurrence of the coalition-like behavior depending on ecological and demographic factors, and test them empirically using data from the five groups of stump-tailed macaques in our study population.
An iron (II) dependent oxygenase performs the last missing step of plant lysine catabolism
Authors: Thompson Mitchell G. , Blake-Hedges Jacquelyn M. , Pereira Jose Henrique , Hangasky John A. , Belcher Michael S. , Moore William M. , Barajas Jesus F. , Cruz-Morales Pablo , Washington Lorenzo J. , Haushalter Robert W. , Eiben Christopher B. , Liu Yuzhong , Skyrud Will , Benites Veronica T. , Barnum Tyler P. , Baidoo Edward E. K. , Scheller Henrik V. , Marletta Michael A. , Shih Patrick M. , Adams Paul D. , Keasling Jay D. 
Published: February 2020

AbstractDue to low abundance in many staple food crops, the essential amino acid lysine must be produced industrially to meet global food supply needs. Despite intensive study, manipulation, and agricultural importance, the steps of plant lysine catabolism beyond the 2-oxoadipate (2OA) intermediate remain undescribed. Recently we described a missing step in the D-lysine catabolic pathway of the bacteriumPseudomonas putidain which 2OA is converted to D-2-hydroxyglutarate (D2HG) via hydroxyglutarate synthase (HglS), an enzyme belonging to the previously uncharacterized DUF1338 protein family. Here we solve the structure of HglS to 1.1Å resolution in the substrate-free form and in complex with 2OA. Structural similarity to hydroxymandelate synthase suggested a successive decarboxylation and intramolecular hydroxylation mechanism forming 2HG in a Fe(II)- and O2-dependent manner, which is validated experimentally. 2OA specificity was mediated by a single arginine (R74), highly conserved across nearly all DUF1338 family proteins, including in 76% of plant enzymes. InArabidopsis thaliana, a DUF1338 homolog is coexpressed with known lysine catabolism enzymes, and mutants show significant germination rate defects consistent with disrupted lysine catabolism. Structural and biochemical analysis of theOryza sativahomolog FLO7 revealed identical activity to HglS despite low sequence identity. Our results suggest that nearly all DUF1338 containing enzymes likely catalyze the same biochemical reaction, exerting the same physiological function across bacteria and eukaryotes.SignificanceTo meet human demands, millions of tons of lysine are produced by bacterial fermentation annually due to its low abundance in staple crops. Here, we show the last missing step of lysine catabolism in nearly all plant endosperms is likely catalyzed by an iron-dependant DUF1338-containing enzyme homologous to the bacterial hydroxyglutarate synthase. Structural and bioninformatic analyses of DUF1338-containing enzymes showed high conservation of critical catalytic and specificity-conferring residues across multiple domains of life despite low sequence identity. These results suggest that the DUF1338 family evolved a specific physiological function within lysine catabolism across multiple domains of life.
Defective influenza A virus RNA products mediate MAVS-dependent upregulation of human leukocyte antigen class I proteins
Authors: Rahim Mir Munir A. , Parsons Brendon D. , Price Emma L. , Slaine Patrick D. , Chilvers Becca L. , Seaton Gregory S. , Wight Andrew , Dey Sayanti , Grandy Shannen L. , Anderson Lauryn E. , Zamorano Cuervo Natalia , Grandvaux Nathalie , Gaglia Marta M. , Kelvin Alyson A. , Khaperskyy Denys A. , McCormick Craig , Makrigiannis Andrew P. 
Published: February 2020

ABSTRACTInfluenza A virus (IAV) increases presentation of class I human leukocyte antigen (HLA) proteins that limit antiviral responses mediated by natural killer (NK) cells, but molecular mechanisms have not yet been fully elucidated. We observed that infection with A/Fort Monmouth/1/1947 (H1N1) IAV significantly increased presentation of HLA-B, -C and -E on lung epithelial cells. Virus entry was not sufficient to induce HLA upregulation, because UV-inactivated virus had no effect. We found that HLA upregulation was elicited by aberrant internally-deleted viral RNAs (vRNAs) known as mini viral RNAs (mvRNAs) and defective interfering RNAs (DI RNAs), which bind to retinoic acid-inducible gene-I (RIG-I) and initiate mitochondrial antiviral signaling (MAVS) protein-dependent antiviral interferon (IFN) responses. Indeed, MAVS was required for HLA upregulation in response to IAV infection or ectopic mvRNA/DI RNA expression. The effect was partially due to paracrine signalling, as we observed that IAV infection or mvRNA/DI RNA-expression stimulated production of IFN-β and IFN-λ1, and conditioned media from these cells elicited a modest increase in HLA surface levels in naïve epithelial cells. HLA upregulation in response to aberrant viral RNAs could be prevented by chemical blockade of IFN receptor signal transduction. While HLA upregulation would seem to be advantageous to the virus, it is kept in check by the viral non-structural 1 (NS1) protein; we determined that NS1 limits cell-intrinsic and paracrine mechanisms of HLA upregulation. Taken together, our findings indicate that aberrant IAV RNAs stimulate HLA presentation, which may aid viral evasion of innate immunity.IMPORTANCEHuman leukocyte antigens (HLA) are cell surface proteins that regulate innate and adaptive immune responses to viral infection by engaging with receptors on immune cells. Many viruses have evolved ways to evade host immune responses by modulating HLA expression and/or processing. Here, we provide evidence that aberrant RNA products of influenza virus genome replication can trigger RIG-I/MAVS-dependent remodeling of the cell surface, increasing surface presentation of HLA proteins known to inhibit the activation of an immune cell known as a natural killer (NK) cell. While this HLA upregulation would seem to be advantageous to the virus, it is kept in check by the viral non-structural 1 (NS1) protein, which limits RIG-I activation and interferon production by the infected cell.