bluuebunny/crossref_metadata_2025_split huggingface dataset:
Translational control of methionine and serine metabolic pathways underpin the paralog-specific phenotypes of Rpl22 ribosomal protein mutants in cell division and replicative longevity
Authors: Maitra Nairita , He Chong , Blank Heidi M. , Tsuchiya Mitsuhiro , Schilling Birgit , Kaeberlein Matt , Aramayo Rodolfo , Kennedy Brian K. , Polymenis Michael 
Published: February 2020

ABSTRACTA long-standing problem is how cells that lack one of the highly similar ribosomal proteins (RPs) often display distinct phenotypes. Some may reflect general effects due to lower growth rate and ribosome levels, but a number of diverse phenotypes cannot be explained through this mechanism. Yeast and other organisms live longer when they lack specific ribosomal proteins, especially of the large 60S subunit of the ribosome. However, longevity is neither associated with the generation time of RP deletion mutants nor with bulk inhibition of protein synthesis. Here, we comprehensively queried actively dividing RP paralog mutants through the cell cycle. Our data link transcriptional, translational, and metabolic changes to phenotypes associated with the loss of paralogous RPs. We uncovered specific translational control of transcripts encoding enzymes of methionine and serine metabolism, which are part of one-carbon (1C) pathways. Cells lacking Rpl22Ap, which are long-lived, have lower levels of metabolites associated with 1C metabolism. Loss of 1C enzymes, such as the serine hydroxymethyltransferase Shm2p increased the longevity of wild type cells. These results provide a molecular basis for paralog-specific phenotypes in ribosomal mutants and underscore the significance of 1C metabolic pathways in mechanisms of cell division and cellular aging. 1C pathways exist in all organisms, including humans, and targeting the relevant enzymes could represent longevity interventions.
Pharmacological inhibition of longevity regulator PAPP-A restrains mesenchymal stromal cell activity
Authors: Mohrin Mary , Liu Justin , Zavala-Solorio Jose , Bhargava Sakshi , Trumble John Maxwell , Brito Alyssa , Hu Dorothy , Brooks Daniel , Bouxsein Mary L. , Baron Roland , Kutskova Yuliya , Freund Adam 
Published: February 2020

AbstractReducing insulin-like growth factor (IGF) signaling is one of the best conserved and characterized mechanisms to extend longevity. Pregnancy associated plasma protein A (PAPP-A) is a secreted metalloprotease that increases IGF availability by cleaving IGF binding proteins. PAPP-A inhibition reduces local IGF signaling, limits the progression of multiple age-related diseases, and extends lifespan, but the mechanisms behind these pleiotropic effects remains unknown. Here, we developed and utilized a PAPP-A neutralizing antibody to discover that adulthood inhibition of this protease reduced collagen and extracellular matrix (ECM) gene expression in multiple tissues in mice. Using bone marrow to explore this effect, we identified mesenchymal stromal cells (MSCs) as the source of PAPP-A and primary responders to PAPP-A inhibition. Short-term treatment with anti-PAPP-A reduced IGF signaling in MSCs, altered MSC expression of collagen/ECM, and decreased MSC number. This affected MSC-dependent functions, decreasing myelopoiesis and osteogenesis. Our data demonstrate that PAPP-A inhibition reduces the activity and number of IGF-dependent mesenchymal progenitor cells and their differentiated progeny, and that this reduction leads to functional changes at the tissue level. MSC-like cells are present in virtually all tissues, and aberrant collagen and ECM production from mesenchymal cells drives aspects of aging and age-related diseases, thus this may be a mechanism by which PAPP-A deficiency enhances lifespan and healthspan.SummaryInhibition of PAPP-A, a regulator of IGF signaling, decreases multi-tissue collagen and extracellular matrix gene expression and modulates mesenchymal stromal cell activity in murine bone marrow.
Dynamic control of visually-guided locomotion through cortico-subthalamic projections
Authors: Adam Elie M. , Johns Taylor , Sur Mriganka 
Published: February 2020

SummaryGoal-directed locomotion requires control signals that propagate from higher-order areas to regulate spinal mechanisms. The cortico-subthalamic hyperdirect pathway offers a short route for cortical information to reach locomotor centers in the brainstem. We developed a task where head-fixed mice run to a visual landmark then stop and wait to collect reward, and examined the role of secondary motor cortex (M2) projections to the subthalamic nucleus (STN) in controlling locomotion. Our modeled behavioral strategy indicates a switching point in behavior or a sudden change from running to stopping, suggesting a critical neuronal control signal at stop locations. Optogenetic activation of M2 axons in STN leads the animal to stop prematurely. By imaging M2 neurons projecting to STN, we find neurons that are active at the onset of stops when executed at the landmark but not when executed spontaneously elsewhere. Our results suggest that the M2-STN pathway can be recruited during visually-guided locomotion to rapidly and precisely control the mesencephalic locomotor region (MLR) through the basal ganglia. By capturing the physiological dynamics through a feedback control model and analyzing neuronal signals in M2, MLR and STN, we find that the cortico-subthalamic projections potentially control MLR activity by differentiating an M2 error signal to ensure fast input-output dynamics.
Microbiome meta-analysis and cross-disease comparison enabled by the SIAMCAT machine-learning toolbox
Authors: Wirbel Jakob , Zych Konrad , Essex Morgan , Karcher Nicolai , Kartal Ece , Salazar Guillem , Bork Peer , Sunagawa Shinichi , Zeller Georg 
Published: February 2020

AbstractThe human microbiome is increasingly mined for diagnostic and therapeutic biomarkers using machine learning (ML). However, metagenomics-specific software is scarce and overoptimistic evaluation and limited cross-study generalization are prevailing issues. To address these, we developed SIAMCAT, a versatile R toolbox for ML-based comparative metagenomics. We demonstrate its capabilities in a meta-analysis of fecal metagenomic studies (10,803 samples). When naively transferred across studies, ML models lost accuracy and disease specificity, which could however be resolved by a novel training set augmentation strategy. This revealed some biomarkers to be disease-specific, others shared across multiple conditions. SIAMCAT is freely available from siamcat.embl.de.
Engineering isoprenoid quinone production in yeast
Authors: Kaur Divjot , Corre Christophe , Alberti Fabrizio 
Published: February 2020

ABSTRACTIsoprenoid quinones are bioactive molecules that include an isoprenoid chain and a quinone head. They are traditionally found to be involved in primary metabolism, where they act as electron transporters, but specialized isoprenoid quinones are also produced by all domains of life. Here, we report the engineering of a baker’s yeast strain,Saccharomyces cerevisiaeEPYFA3, for the production of isoprenoid quinones. Our yeast strain was developed through overexpression of the shikimate pathway in a well-established recipient strain (S. cerevisiaeEPY300) where the mevalonate pathway is overexpressed. As a proof of concept, our new host strain was used to overproduce the endogenous isoprenoid quinone coenzyme Q6, resulting in a final four-fold production increase. EPYFA3 represents a valuable platform for the heterologous production of high value isoprenoid quinones. EPYFA3 will also facilitate the elucidation of isoprenoid quinone biosynthetic pathways.Abstract Figure
Histopathological aspects of induced resistance byPseudomonas protegensCHA0 and β-aminobutyric acid in wheat againstPuccinia triticina
Authors: Bellameche Fares , Jasim Mohammed A. , Mauch-Mani Brigitte , Mascher Fabio 
Published: February 2020

AbstractAfter perception of specific biotic or abiotic stimuli, such as root colonization by rhizobacteria or selected chemicals, plants are able to enhance their basal resistance against pathogens. Due to its sustainability, such induced resistance is highly valuable for disease management in agriculture. Here we study an example of resistance against wheat-leaf rust induced byPseudomonas protegensCHA0 (CHA0) and β-aminobutyric acid (BABA), respectively. Seed dressing with CHA0 reduced the number of sporulating pustules on the leaves and the expression of resistance was visible as necrotic or chlorotic flecks. Moreover, a beneficial effect of CHA0 on growth was observed in wheat seedlings challenged or not with leaf rust. BABA was tested at 10, 15 and 20 mM and a dose-dependent reduction of leaf rust infection was observed with the highest level of protection at 20 mM. However, BABA treatment repressed plant growth at 20 mM. Balancing between BABA-impact on plant growth and its protective capacity, we selected 15 mM as suitable concentration to protect wheat seedlings against leaf rust with the least impact on vegetative growth. To understand the mechanisms behind the observed resistance, we have studied the histological aspects of the fungal infection process. Our results showed that the p re-entry process was not affected by the two resistance inducers. However, both treatments reduced fungal penetration and haustoria formation. The timing and the amplitude of the resistance reactions was different after bacterial or chemical induction, leading to different levels of resistance to leaf rust. During fungal colonization of the tissues, a high deposition of callose and the accumulation of H2O2in both CHA0-and BABA-treated plants pointed to an important contribution to resistance.
A Precision Medicine Approach to Stress Testing Using Metabolomics and Microribonucleic Acids
Authors: Limkakeng Alexander T. , Rowlette Laura-Leigh , Hatch Ace , Nixon Andrew B. , Ilkayeva Olga , Corcoran David L. , Modliszewski Jennifer L. , Griffin S. Michelle , Tsalik Ephraim L. , Ginsburg Geoffrey S. , Voora Deepak 
Published: February 2020

ABSTRACTBackgroundAcute coronary syndrome (ACS) is a growing global health problem, and precision medicine techniques hold promise for the development of diagnostic indicators of ACS. In this pilot, we sought to assess the utility of an integrated analysis of metabolomic and microRNA data in peripheral blood to distinguish patients with abnormal cardiac stress testing from matched controls.MethodsWe used prospectively collected samples from emergency department (ED) patients placed in an ED-based observation unit who underwent stress testing for ACS. We isolated microRNA and quantified metabolites from plasma collected before and after stress testing in patients with myocardial ischemia on stress testing versus those with normal stress tests. The combined metabolomic and microRNA data were analyzed jointly for case (ischemia) and 1:1 matched control patients in a supervised, dimension-reducing discriminant analysis. Two integrative models were implemented: a baseline model utilizing data collected prior to stress-testing (T0) and a stress-delta model, which included the difference between post-stress test (T1) and pre-stress test (T0).ResultsSeven case patients with myocardial ischemia on ED cardiac stress testing (6 females, 85% Caucasian, mean Thrombolysis In Myocardial Infarction Score=3, 4 patients ultimately received percutaneous coronary intervention) were 1:1 age and sex-matched to controls. Several metabolites and microRNAs were differentially expressed between cases and controls. Integrative analysis of the baseline levels of metabolites and microRNA expression showed modest performance for distinguishing cases from controls with an overall error rate of 0.143. The stress-delta model showed worse performance for distinguishing cases from controls, with an overall error rate of 0.500.ConclusionsGiven our small sample size, results are hypothesis-generating. However, this pilot study shows a potential method for a precision medicine approach to cardiac stress testing in patients undergoing workup for ACS.
Two antagonistic microtubule targeting drugs act synergistically to kill cancer cells
Authors: Peronne Lauralie , Denarier Eric , Rai Ankit , Prudent Renaud , Vernet Audrey , Suzanne Peggy , Ramirez-Rios Sacnicté , Michallet Sophie , Guidetti Mélanie , Vollaire Julien , Lucena-Agell Daniel , Ribba Anne-Sophie , Josserand Véronique , Coll Jean-Luc , Dallemagne Patrick , Díaz J. Fernando , Oliva María Ángela , Sadoul Karin , Akhmanova Anna , Andrieux Annie , Lafanechère Laurence 
Published: February 2020

AbstractPaclitaxel is a microtubule stabilizing agent and a successful drug for cancer chemotherapy inducing, however, adverse effects. To reduce the effective dose of paclitaxel, we searched for drugs which could potentiate its therapeutic effect. We have screened a chemical library and selected Carba1, a carbazolone, which exerts synergistic cytotoxic effects on tumor cells grownin vitro, when co-administrated with a low dose of paclitaxel. Carba1 targets the colchicine binding-site of tubulin and is a microtubule-destabilizing agent. The Carba1-induced modulation of microtubule dynamics increases the accumulation of fluorescent paclitaxel inside microtubules, providing a mechanistic explanation of the observed synergy between Carba1 and paclitaxel. The synergistic effect of Carba1 with paclitaxel on tumor cell viability was also observedin vivoin xenografted mice. Thus, a new mechanism favoring paclitaxel accumulation in microtubules can be transposed toin vivomouse cancer treatments, paving the way for new therapeutic strategies combining low doses of microtubule targeting agents with opposite mechanisms of action.
In situstructure determination of virus capsids imaged within cell nuclei by correlative light and cryo-electron tomography
Authors: Vijayakrishnan Swetha , McElwee Marion , Loney Colin , Rixon Frazer , Bhella David 
Published: February 2020

AbstractCryo electron microscopy (cryo-EM), a key method for structure determination involves imaging purified material embedded in vitreous ice. Images are then computationally processed to obtain three-dimensional structures at atomic resolution. There is increasing interest in extending structural studies by cryo-EM into the cell, where biological structures and processes may be imaged in context. The limited penetrating power of electrons prevents imaging of thick specimens (>500 nm) however. Cryo-sectioning methods employed to overcome this are technically challenging, subject to artefacts or involve specialised equipment of limited availability. Here we describe the first structure of herpesvirus capsids determined by sub-tomogram averaging from nuclei of eukaryotic cells, achieved by cryo-electron tomography (cryo-ET) of re-vitrified cell sections prepared using the Tokuyasu method. Our reconstructions reveal that the capsid associated tegument complex is present on capsids prior to nuclear egress. We show that this approach to cryogenic imaging of cells is suited to both correlative light/electron microscopy and 3D structure determination.
FluoSim: simulator of single molecule dynamics for fluorescence live-cell and super-resolution imaging of membrane proteins
Authors: Lagardère Matthieu , Chamma Ingrid , Bouilhol Emmanuel , Nikolski Macha , Thoumine Olivier 
Published: February 2020

AbstractFluorescence live-cell and super-resolution microscopy methods have considerably advanced our understanding of the dynamics and mesoscale organization of macro-molecular complexes that drive cellular functions. However, different imaging techniques can provide quite disparate information about protein motion and organization, owing to their respective experimental ranges and limitations. To address these limitations, we present here a unified computer program that allows one to model and predict membrane protein dynamics at the ensemble and single molecule level, so as to reconcile imaging paradigms and quantitatively characterize protein behavior in complex cellular environments. FluoSim is an interactive real-time simulator of protein dynamics for live-cell imaging methods including SPT, FRAP, PAF, and FCS, and super-resolution imaging techniques such as PALM, dSTORM, and uPAINT. The software, thoroughly validated against experimental data on the canonical neurexin-neuroligin adhesion complex, integrates diffusion coefficients, binding rates, and fluorophore photo-physics to calculate in real time the distribution of thousands of independent molecules in 2D cellular geometries, providing simulated data of protein dynamics and localization directly comparable to actual experiments.
Pro-inflammatory cytokines drive deregulation of potassium channel expression in primary synovial fibroblasts
Authors: Haidar Omar , O’Neill Nathanael , Staunton Caroline A. , Bavan Selvan , O’Brien Fiona , Zouggari Sarah , Sharif Umar , Mobasheri Ali , Kumagai Kosuke , Barrett-Jolley Richard 
Published: February 2020

AbstractThe synovium secretes synovial fluid, but is also richly innervated with nociceptors and acts as a gateway between avascular joint tissues and the circulatory system. Resident fibroblast-like synoviocytes’ (FLS) calcium-activated potassium channels (KCa) change in activity in arthritis models and this correlates with FLSactivation.ObjectiveTo investigate this activation in anin vitromodel of inflammatory arthritis; 72hr treatment with cytokines TNFα and IL1β.MethodsFLS cells were isolated from rat synovial membranes. We analysed global changes in FLS mRNA by RNA-sequencing and then focused on FLS ion channels genes and corresponding FLS electrophysiological phenotype, finally modelling data with Ingenuity Pathway Analysis (IPA) and MATLAB.ResultsIPA showed significant activation of inflammatory, osteoarthritic and calcium signalling canonical pathways by cytokines, and we identified ~200 channel gene transcripts. The large KCa(BK) channel consists of the pore forming Kcnma1 together with β-subunits. Following cytokine treatment, a significant increase in Kcnma1 RNA abundance was detected by qPCR and changes in several ion channels were detected by RNA-sequencing, including a loss of BK channel β-subunit expression Kcnmb1/2 and increase in Kcnmb3. In electrophysiological experiments, there was a decrease in overall current density at 20mV without change in chord conductance at this potential.ConclusionTNFα and IL1β treatment of FLS in vitro recapitulated several common features of inflammatory arthritis at the transcriptomic level, including increase in Kcnma1 and Kcnmb3 gene expression.
The relationship between resting-state functional connectivity, antidepressant discontinuation and depression relapse
Authors: Berwian Isabel M. , Wenzel Julia G. , Kuehn Leonie , Schnuerer Inga , Kasper Lars , Veer Ilya M. , Seifritz Erich , Stephan Klaas E. , Walter Henrik , Huys Quentin J. M. 
Published: February 2020

AbstractThe risk of relapsing into depression after stopping antidepressants is high, but no established predictors exist. Resting-state functional magnetic resonance imaging (rsfMRI) measures may help predict relapse and identify the mechanisms by which relapses occur. rsfMRI data were acquired from healthy controls and from patients with remitted major depressive disorder on antidepressants. Patients were assessed a second time either before or after discontinuation of the antidepressant, and followed up for six months to assess relapse. A seed-based functional connectivity analysis was conducted focusing on the left subgenual anterior cingulate cortex and left posterior cingulate cortex. Seeds in the amygdala and dorsolateral prefrontal cortex were explored. 44 healthy controls (age: 33.8 (10.5), 73% female) and 84 patients (age: 34.23 (10.8), 80% female) were included in the analysis. 29 patients went on to relapse and 38 remained well. The seed-based analysis showed that discontinuation resulted in an increased functional connectivity between the right dorsolateral prefrontal cortex and the parietal cortex in non-relapsers. In an exploratory analysis, this functional connectivity predicted relapse risk with a balanced accuracy of 0.86. Further seed-based analyses, however, failed to reveal differences in functional connectivity between patients and controls, between relapsers and non-relapsers before discontinuation and changes due to discontinuation independent of relapse. In conclusion, changes in the connectivity between the dorsolateral prefrontal cortex and the posterior default mode network were associated with and predictive of relapse after open-label antidepressant discontinuation. This finding requires replication in a larger dataset.
Type II Fusarium head blight susceptibility factor identified in wheat
Authors: Hales B. , Steed A. , Giovannelli V. , Burt C. , Lemmens M. , Molnár-Láng M. , Nicholson P. 
Published: February 2020

AbstractFusarium head blight (FHB) causes significant grain yield and quality reductions in wheat and barley. Most wheat varieties are incapable of preventing FHB spread through the rachis, but disease is typically limited to individually infected spikelets in barley. We point inoculated wheat lines possessing barley chromosome introgressions to test whether FHB resistance could be observed in a wheat genetic background. The most striking differential was between 4H(4D) substitution and 4H addition lines. The 4H addition line was similarly susceptible to the wheat parent, but the 4H(4D) substitution line was highly resistant, which suggests that there is an FHB susceptibility factor on wheat chromosome 4D. Point inoculation of Chinese Spring 4D ditelosomic lines demonstrated that removing 4DS results in high FHB resistance. We genotyped four Chinese Spring 4DS terminal deletion lines to better characterise the deletions in each line. FHB phenotyping indicated that lines del4DS-2 and del4DS-4, containing smaller deletions, were susceptible and had retained the susceptibility factor. Lines del4DS-3 and del4DS-1 contain larger deletions and were both significantly more resistant, and hence had presumably lost the susceptibility factor. Combining the genotyping and phenotyping results allowed us to refine the susceptibility factor to a 31.7 Mbp interval on 4DS.HighlightWe have identified a Type II Fusarium head blight susceptibility factor on the short arm of wheat chromosome 4D and refined its position to a 31.7 Mbp interval.
Vitamin D regulates MerTK-dependent phagocytosis in human myeloid cells
Authors: Clarke Jelani , Yaqubi Moein , Futhey Naomi C. , Sedaghat Sara , Baufeld Caroline , Blain Manon , Baranzini Sergio , Butovsky Oleg , White John H. , Antel Jack , Healy Luke M. 
Published: February 2020

AbstractVitamin D deficiency is a major environmental risk factor for the development of multiple sclerosis (MS). The major circulating metabolite of vitamin D (25OHD) is converted to the active form (calcitriol) by the hydroxylase enzymeCYP27B1. In MS lesions the tyrosine kinase MerTK expressed by microglia and macrophages regulates phagocytosis of myelin debris and apoptotic cells that can accumulate and inhibit tissue repair and remyelination. We show that calcitriol downregulates MerTK mRNA and protein expression in adult human microglia and monocyte-derived macrophages, thereby inhibiting myelin phagocytosis and apoptotic cell clearance. Proinflammatory myeloid cells express high levels ofCYP27B1compared to homeostatic (TGFβ-treated) myeloid cells. Only proinflammatory cells in the presence of TNF-α generate calcitriol from 25OHD, resulting in repression of MerTK expression and function. The selective production of calcitriol in proinflammatory myeloid cells leading to downregulation of MerTK-mediated phagocytosis has the potential to reduce the risk for auto-antigen presentation while retaining the phagocytic ability of homeostatic myeloid cells, thereby contributing to inflammation reduction and enhanced tissue repair.