bluuebunny/crossref_metadata_2025_split huggingface dataset:
Polymorphisms in HIV-1nefare associated with plasma concentration of biomarkers of endothelial activation
Authors: Mezoh Genevieve , Lutchman Nereshni , Cave Eleanor M , Prigge Katherine , Worsley Catherine , Martinson Neil , Mayne Elizabeth , Lambson Bronwen E , Moore Penny L , Crowther Nigel J 
Published: October 2022

AbstractInfection with HIV is associated with an increased risk of cardiovascular disease (CVD), which may be mediated by the effect of the viral proteins, Nef and Tat, on inflammation and endothelial activation. The viral genes coding for Nef and Tat contain numerous polymorphisms, which we hypothesised may be differentially associated with endothelial activation. Therefore, our aim was to assess the association of these polymorphisms with endothelial activation and inflammation in subjects infected with HIV-1.The HIV-1nefandtatgenes were sequenced from clinical isolates from 31 and 34 patients, respectively. Plasma concentration of biomarkers of endothelial activation (intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), endothelial leukocyte adhesion molecule-1 (E-selectin), monocyte chemoattractant protein-1 (MCP-1) and von Willebrand factor (vWF)), and biomarkers of inflammation (tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and interleukin-8 (IL-8)), were measured. Analysis of HIV-1nefgene sequences identified five polymorphisms (V16I, H40Y, T50A,H, S169N and H188Q,S) that were each significantly (p<0.05) associated with ICAM-1 plasma concentration. An additive effect of these variants on plasma ICAM-1 concentration (p=0.004 for trend), was observed. No significant associations were seen between Tat amino acid residues and plasma concentration of markers of endothelial activation and inflammation. These are the first humanin vivodata that support the hypothesis thatnefgene polymorphisms impact endothelial function.ImportanceCardiovascular disease (CVD) is a leading cause of mortality in adults living with HIV, which may in part be due to endothelial activation and inflammation caused by the viral proteins, Nef and Tat. However, there is no data from humans supporting the CVD-associated Nef and Tat hypothesis, and assays for accurately measuring Nef and Tat plasma concentrations are not currently available. Therefore, we hypothesized that polymorphisms in thenefandtatgenes of clinical viral isolates may be associated with host plasma markers of endothelial activation and inflammation. Our results show that this was the case, with fivenefpolymorphisms showing both individual and additive association with plasma concentration of ICAM-1. The HIV-1Tatgene, however, showed no significant association with plasma concentrations of markers of endothelial activation and inflammation. This is the first human study to directly link Nef to endothelial activation and to provide a possible screening tool i.e.,nefgenotyping, for identifying individuals at high risk of endothelial-based diseases.
The Eyes Absent family members EYA4 and EYA1 promote PLK1 activation and successful mitosis through tyrosine dephosphorylation
Authors: Nelson Christopher B. , Rogers Samuel , Roychoudhury Kaushik , Tan Yaw Sing , Atkinson Caroline J. , Sobinoff Alexander P. , Tomlinson Christopher G. , Hsu Anton , Lu Robert , Dray Eloise , Haber Michelle , Fletcher Jamie I. , Cesare Anthony J. , Hegde Rashmi S. , Pickett Hilda A. 
Published: October 2022

AbstractThe Eyes Absent family of proteins (EYA1-4) are a biochemically unique group of tyrosine phosphatases known to be tumour promoting across a range of cancer types. To date, the molecular targets of EYA phosphatase activity remain largely uncharacterised. Here, we identify Polo-like kinase 1 (PLK1) as a direct interactor and phosphatase substrate of both EYA4 and EYA1, with pY445 on PLK1 being the primary target site. EYA-mediated dephosphorylation of PLK1 in the G2 phase of the cell cycle is required for centrosome maturation, PLK1 localization to centrosomes, and polo-box domain (PBD) dependent interactions between PLK1 and the PLK1-activating proteins BORA and CEP192. Molecular dynamics simulations support the rationale that pY445 confers a structural impairment to PBD-substrate interactions that is relieved by EYA-mediated dephosphorylation. Depletion of EYA4 or EYA1, or chemical inhibition of EYA phosphatase activity, dramatically reduces PLK1 activation, causing mitotic defects and cell death. Overall, we have characterized a novel phosphotyrosine signalling network governing PLK1 and mitosis. This work provides a mechanism of cell killing for EYA phosphatase inhibitors with important therapeutic implications.
The glyoxylate shunt protein ICL-1 protects from mitochondrial superoxide stress through activation of the mitochondrial unfolded protein response
Authors: Wang Guoqiang , Laranjeiro Ricardo , LeValley Stephanie , Van Raamsdonk Jeremy M. , Driscoll Monica 
Published: October 2022

ABSTRACTEliminating mitochondrial superoxide dismutase (SOD) causes neonatal lethality in mice and death of flies within 24 hours after eclosion. Deletion of mitochondrialsodgenes inC. elegansimpairs fertility as well, but surprisingly is not detrimental to survival of progeny generated. The comparison of metabolic pathways among mouse, flies and nematodes reveals that mice and flies lack the glyoxylate shunt. Here we show that ICL-1, the only protein of the glyoxylate shunt, is critical for protection against embryonic lethality resulting from elevated levels of mitochondrial superoxide. In exploring the mechanism by which ICL-1 protects against ROS-mediated embryonic lethality, we find that ICL-1 is required for the efficient activation of mitochondrial unfolded protein response (UPRmt) and that the UPRmtis essential to suppress embryonic/neonatal lethality in animals lacking mitochondrial SOD. In sum, we identified a biochemical pathway that highlights a molecular strategy for combating superoxide consequences in cells.
GenSLMs: Genome-scale language models reveal SARS-CoV-2 evolutionary dynamics
Authors: Zvyagin Maxim , Brace Alexander , Hippe Kyle , Deng Yuntian , Zhang Bin , Bohorquez Cindy Orozco , Clyde Austin , Kale Bharat , Perez-Rivera Danilo , Ma Heng , Mann Carla M. , Irvin Michael , Gregory Pauloski J. , Ward Logan , Hayot-Sasson Valerie , Emani Murali , Foreman Sam , Xie Zhen , Lin Diangen , Shukla Maulik , Nie Weili , Romero Josh , Dallago Christian , Vahdat Arash , Xiao Chaowei , Gibbs Thomas , Foster Ian , Davis James J. , Papka Michael E. , Brettin Thomas , Stevens Rick , Anandkumar Anima , Vishwanath Venkatram , Ramanathan Arvind 
Published: October 2022

ABSTRACTWe seek to transform how new and emergent variants of pandemiccausing viruses, specifically SARS-CoV-2, are identified and classified. By adapting large language models (LLMs) for genomic data, we build genome-scale language models (GenSLMs) which can learn the evolutionary landscape of SARS-CoV-2 genomes. By pretraining on over 110 million prokaryotic gene sequences and finetuning a SARS-CoV-2-specific model on 1.5 million genomes, we show that GenSLMs can accurately and rapidly identify variants of concern. Thus, to our knowledge, GenSLMs represents one of the first whole genome scale foundation models which can generalize to other prediction tasks. We demonstrate scaling of GenSLMs on GPU-based supercomputers and AI-hardware accelerators utilizing 1.63 Zettaflops in training runs with a sustained performance of 121 PFLOPS in mixed precision and peak of 850 PFLOPS. We present initial scientific insights from examining GenSLMs in tracking evolutionary dynamics of SARS-CoV-2, paving the path to realizing this on large biological data.
Mycelial nutrient transfer promotes bacterial co-metabolic organochlorine pesticide degradation in nutrient-deprived environments
Authors: Khan Nelson , Muge Edward , Mulaa Francis J. , Wamalwa Benson , von Bergen Martin , Jehmlich Nico , Wick Lukas Y. 
Published: October 2022

AbstractBiotransformation of soil organochlorine pesticides (OCP) is often impeded by a lack of nutrients relevant for bacterial growth and/or co-metabolic OCP biotransformation. By providing space-filling mycelia, fungi promote contaminant biodegradation by facilitating bacterial dispersal and the mobilization and release of nutrients in the mycosphere. We here tested whether mycelial nutrient transfer from nutrient-rich to nutrient-deprived areas facilitates bacterial OCP degradation in a nutrient-deficient habitat. The legacy pesticide hexachlorocyclohexane (HCH), a non-HCH-degrading fungus (Fusarium equisetiK3) and a co-metabolically HCH-degrading bacterium (Sphingomonassp. S8) isolated from the same HCH-contaminated soil were used in spatially structured model ecosystems. Using13C-labelled fungal biomass and protein-based stable isotope probing (protein-SIP), we traced the incorporation of13C fungal metabolites into bacterial proteins while simultaneously determining the biotransformation of the HCH isomers. The relative isotope abundance (RIA, 7.1 – 14.2%), labeling ratio (LR, 0.13 – 0.35), and the shape of isotopic mass distribution profiles of bacterial peptides indicated the transfer of13C-labeled fungal metabolites into bacterial proteins. Distinct13C incorporation into the haloalkane dehalogenase (linB) and 2,5-dichloro-2,5-cyclohexadiene-1,4-diol dehydrogenase (LinC), as key enzymes in metabolic HCH degradation, underpin the role of mycelial nutrient transport and fungal-bacterial interactions for co-metabolic bacterial HCH degradation in heterogeneous habitats. Nutrient uptake from mycelia increased HCH removal by twofold as compared to bacterial monocultures. Fungal-bacterial interactions hence may play an important role in the co-metabolic biotransformation of OCP or recalcitrant micropollutants (MPs).
A quantitative fluorescence-based approach to study mitochondrial protein import
Authors: Jain Naintara , Gomkale Ridhima , Bernhard Olaf , Rehling Peter , Cruz-Zaragoza Luis Daniel 
Published: October 2022

AbstractMitochondria play central roles in cellular energy production and metabolism. Most of the proteins that are required to carry out these functions are synthesized in the cytosol and imported into mitochondria. A growing number of metabolic disorders arising from mitochondrial dysfunction can be traced to errors in mitochondrial protein import. The mechanisms underlying the import of precursor proteins are commonly studied by using radioactively-labeled precursor proteins, which are imported into purified mitochondria. Here, we establish a fluorescence-based import assay to analyze protein import into mitochondria. We show that fluorescently-labeled precursors enable import analysis with similar sensitivity to those using radioactive precursors, yet they provide the advantage of quantifying import with picomole resolution. We adapted the import assay to a 96-well plate format allowing for fast analysis in a screening-compatible format. Moreover, we show that fluorescently labeled precursors can be used to monitor the assembly of the F1F0 ATP-synthase in purified mitochondria. Thus, we provide a sensitive fluorescence-based import assay that enables quantitative and fast-import analysis.
FBXO7/ntc and USP30 antagonistically set the ubiquitination threshold for basal mitophagy and provides a target for Pink1 phosphorylationin vivo
Authors: Sanchez-Martinez Alvaro , Martinez Aitor , Whitworth Alexander J. 
Published: October 2022

AbstractFunctional analyses of genes linked to heritable forms of Parkinson’s disease (PD) have revealed fundamental insights into the biological processes underpinning pathogenic mechanisms. Mutations inPARK15/FBXO7cause autosomal recessive PD and FBXO7 has been shown to regulate mitochondrial homeostasis. We investigated the extent to which FBXO7 and itsDrosophilaorthologue, ntc, share functional homology and explored its role in mitophagyin vivo. We show thatntcmutants partially phenocopyPink1andparkinmutants andntcoverexpression supressesparkinphenotypes. Furthermore, ntc can modulate basal mitophagy in a Pink1- and parkin-independent manner by promoting the ubiquitination of mitochondrial proteins, a mechanism that is opposed by the deubiquitinase USP30. This basal ubiquitination serves as the substrate for Pink1-mediated phosphorylation which triggers stress-induced mitophagy. We propose that FBXO7/ntc works in equilibrium with USP30 to provide a checkpoint for mitochondrial quality control in basal conditionsin vivoand presents a new avenue for therapeutic approaches.
Post-translational modification by the Pgf glycosylation machinery modulatesStreptococcus mutansphysiology and virulence
Authors: de Mojana di Cologna Nicholas , Andresen Silke , Samaddar Sandip , Archer-Hartmann Stephanie , Ganguly Tridib , Kajfasz Jessica K. , Garcia Bruna A. , Saengpet Irene , Peterson Alexandra M. , Azadi Parastoo , Szymanski Christine M. , Lemos José A. , Abranches Jacqueline 
Published: October 2022

AbstractStreptococcus mutansis a keystone pathogen of dental caries, and the ability to form biofilms is essential for its pathogenicity. We identified a glycosylation machinery (Pgf) inS. mutansthat post-translationally modifies two surface-associated adhesins, Cnm and WapA. The fourpgfgenes (pgfS,pgfM1,pgfE,andpgfM2) are part ofS. mutanscore genome and we hypothesized that the scope of Pgf goes beyond Cnm and WapA. By inactivating eachpgfgene individually or creating a quadruplepgfmutant inS. mutansOMZ175, we showed that the Pgf machinery is important for biofilm formation. Compared to OMZ175, differences in surface charge, membrane stability, and genetic competence were also observed for most mutants. Importantly,in silicoanalyses and tunicamycin MIC assays suggest a functional redundancy between the Pgf machinery and the rhamnose-glucose polysaccharide synthesis pathway. Using a rat oral colonization model, we showed a 10-fold reduction in recovered CFUs for thepgfquadruple mutant compared to OMZ175. Finally, using Cnm as a model, we showed by glycoproteomics analyses that Cnm is heavily modified with N-acetyl hexosamine in OMZ175 whereas phosphorylations were observed for thepgfSmutant. Our findings indicate that the Pgf machinery participates in important aspects ofS. mutanspathobiology.Graphical AbstractAbbreviated summaryIn this study, we demonstrate that the Pgf glycosylation machinery ofStreptococcus mutans, a keystone pathogen of dental caries, regulates several aspects of bacterial pathophysiology that ultimately contribute toS. mutansfitness in oral colonization experiments. Using the heavily glycosylated Cnm adhesin as a model, we found that inactivation of the glycosyltransferase PgfS results in loss of Cnm glycosylation, but instead, Cnm became heavily phosphorylated, suggesting a crosstalk/competition between these two post-translational modification mechanisms.
A novel image-based approach for soybean seed phenotyping using machine learning techniques
Authors: de Carvalho Miranda Melissa Cristina , Aono Alexandre Hild , Pinheiro José Baldin 
Published: October 2022

AbstractSoybean is one of the most important sources of protein and vegetable oil in the world. Given its increasing demand, the increment in yield has only been possible due to investments in research and production technology, especially in breeding programs. One of the main factors influencing soybean yield is the seed morphology; however, its analyses are hampered by the lack of efficient computational approaches with not only accurate results, but also a high flexibility to user preferences and needs. In this context, the present work provides a methodological framework for: (i) seed segmentation in soybean images; (ii) seed morphological evaluation; and (iii) image-based prediction of the hundred-seed weight trait. We used genotypes from a partial diallel cross design, which aimed at obtaining genotypes with high agronomic performance. In addition to the measurement of the hundred-seed weight, we collected RGB images of seeds of each plot. For image segmentation, we created an in-house image processing pipeline, which enabled a full morphological seed evaluation. For predicting the hundred-seed weight, we compared different machine learning algorithms using as input the morphological characteristics obtained, and also features from state-of-the-art convolutional neural network (CNN) architectures. The image segmentation methodology showed to be highly efficient, as more than 98% of the seeds in the images were correctly identified. Even if the seeds were close, the segmentation strategy could separate them into independent image components. In addition to supplying a highly accurate decision support system for soybean breeders, we verified the morphological phenotyping adaptability in other plant species, fully assessing the pipeline generalization. We consider the use of this methodology highly advantageous, as the method is entirely based on widely used morphological operations, which results in an easy implementation and low computational costs. Using these morphological measures, we could estimate machine learning models for predicting the hundred-seed weight, achieving considerable predictive accuracy. The same results were observed for CNN-obtained features, showing the efficiency of the morphological measurements as feature extractors. The possibility of obtaining seed morphological characteristics provides a valuable tool for the continuous and efficient development of new soybean cultivars in breeding programs aimed at long-term genetic gain. Additionally, through a faster seed image acquisition workflow, with less chance of errors and low cost, it is also possible to make predictions of important soybean characteristics. The work conducted has the potential to help future research and the industry to develop automated phenotyping tools, incorporating the proposed analytical workflows.
Cropbox: a declarative crop modeling framework
Authors: Yun Kyungdahm , Kim Soo-Hyung 
Published: October 2022

AbstractCrop models mirror our knowledge on cropsin silico. Therefore, crop modeling inherits common issues of software engineering and often suffers from technical debts. We introduce a new crop modeling framework: Cropbox as a declarative domain-specific language. Recognizing that a crop model is fundamentally an integrated network of generalized state variables, we developed the framework to encapsulate abstract primitives for representing variables, systems, and functions that are essential to crop modeling workflows. With a constrained syntax, high-level model specifications are automatically translated into low-level host code written in Julia programming language. This allows complex crop models to become more accessible and transparent for modelers to build and use. We highlight key capabilities of the Cropbox framework through specific case studies featuring a coupled leaf gas-exchange model and a process-based crop simulation model. We also illustrate potential extensions of the framework to support functional-structural plant modeling (FSPM) using a 3D root architectural model as an example.
HES1 contributes to high salt stress response as an enhancer of NFAT5-DNA binding
Authors: Ryuno Hiroki , Hanafusa Yusuke , Naguro Isao , Ichijo Hidenori 
Published: October 2022

AbstractHigh salt conditions and subsequent hyperosmolarity are injurious cellular stresses but can activate immune signaling. Nuclear factor of activated T-cells 5 (NFAT5) is an essential transcription factor that induces osmoprotective genes such as aldose reductase (AR) and betaine-GABA transporter 1 (BGT1). High salt stress-mediated NFAT5 activation is also reported to accelerate the inflammatory response and autoimmune diseases. However, the systemic regulation of NFAT5 remains unclear. Here, we performed a genome-wide siRNA screen to comprehensively identify the upstream factors of NFAT5. We monitored NFAT5 nuclear translocation and identified one of the Notch signaling effectors, Hairy and enhancer of split-1 (HES1), as a novel positive regulator of NFAT5. HES1 was induced by high salinity via ERK signaling and facilitated NFAT5 recruitment to its target promoter region, resulting in the proper induction of osmoprotective genes and cytoprotection under high salt stress. These findings suggest that although HES1 is well known as a transcriptional repressor, it positively regulates NFAT5-dependent transcription in the context of a high salinity/hyperosmotic response.One Sentence SummaryHES1 contributes to high salinity/hyperosmotic response through positive regulation of NFAT5-dependent transcription.
Heart failure risk is accurately predicted by certain serum proteins
Authors: Emilsson V , Jonsson BG , Gudmundsdottir V , Axelsson GT , Frick EA , Jonmundsson T , Steindorsdottir AE , Launer LJ , Aspelund T , Kortekaas KA , Lindeman JH , Lamb JR , Jennings LL , Gudnason V 
Published: October 2022

AbstractAimTo investigate the utility of serum proteins to predict new-onset heart failure (HF), including those with reduced or preserved ejection fraction (HFrEF or HFpEF), with or without the consideration of known HF-associated clinical variables.Methods and resultsThe study included 612 participants with HF events from the prospective population-based AGES-Reykjavik cohort of the elderly (N = 5457), 440 of whom were incident cases, with a median follow-up time of 5.45 years. The incident HF population with echocardiographic data included patients with HFrEF (n = 167) and HFpEF (n = 188). The least absolute shrinkage and selection operator (LASSO) model in conjunction with bootstrap resampling validation (500 replications) were used to select predictor variables based on the analysis of 4782 serum proteins and numerous clinical variables related to HF. In at least 80% of bootstrap replications, a subset of 8 to 13 serum proteins had non-zero coefficients for predicting all incident HF, HFpEF, or HFrEF separately. We used C-statistics to assess the goodness of fit when modeling a prognostic risk score for incident HF. In the null model, which did not take age, sex or clinical variables into account, 13 proteins combined had a C-index of 0.80 for all incident HF, whereas for incident HFpEF and HFrEF, the C-index for a subset of 8 or 10 protein predictors combined was 0.78 and 0.80, respectively. The concordance gain for each set of protein predictors was also investigated in the context of the approved biomarker NPPB as well as a number of clinical variables such as Framingham risk score components and calcium in the coronary artery and thoracic aorta. We show that these proteins improve prediction of future HF events even when a large number of HF-associated clinical variables are not included in the model.ConclusionA small number of circulating proteins were found to accurately predict new-onset HF when no demographic or other information was included, and they also improved the prediction when the main known biomarker NPPB and many HF-associated clinical risk factors of the condition were taken into account.