bluuebunny/crossref_metadata_2025_split huggingface dataset:
2-deoxyglucose transiently inhibits yeast AMPK signaling and triggers glucose transporter endocytosis, potentiating the drug toxicity
Authors: Laussel Clotilde , Albanèse Véronique , García-Rodríguez Francisco Javier , Ballin Alberto , Defenouillère Quentin , Léon Sébastien 
Published: March 2022

Abstract2-deoxyglucose is a glucose analog that impacts many aspects of cellular physiology. After its uptake and its phosphorylation into 2-deoxyglucose-6-phosphate (2DG6P), it interferes with several metabolic pathways including glycolysis and protein N-glycosylation. Despite this systemic effect, resistance can arise through strategies that are only partially understood. In yeast, 2DG resistance is often associated with mutations causing increased activity of the yeast 5’-AMP activated protein kinase (AMPK), Snf1. Here we focus on the contribution of a Snf1 substrate in 2DG resistance, namely the alpha-arrestin Rod1 involved in nutrient transporter endocytosis. We report that 2DG triggers the endocytosis of many plasma membrane proteins, mostly in a Rod1-dependent manner. Rod1 participates in 2DG-induced endocytosis because 2DG, following its phosphorylation by hexokinase Hxk2, triggers changes in Rod1 post-translational modifications and promotes its function in endocytosis. Mechanistically, this is explained by a transient, 2DG-induced inactivation of Snf1/AMPK by protein phosphatase 1 (PP1). We show that 2DG-induced endocytosis is detrimental to cells, and the lack of Rod1 counteracts this process by stabilizing glucose transporters at the plasma membrane. This facilitates glucose uptake, which may help override the metabolic blockade caused by 2DG, and 2DG export - thus terminating the process of 2DG detoxification. Altogether, these results shed a new light on the regulation of AMPK signaling in yeast and highlight a remarkable strategy to bypass 2DG toxicity involving glucose transporter regulation.Author summaryIn this article, we study the resistance to a drug named 2-deoxyglucose (2DG). 2DG is an efficient inhibitor of several metabolic pathways, particularly glycolysis which is of prime importance for tumor cell proliferation. Cancer cells but also cells from other organisms can develop various resistance strategies that only being unraveled. Here, using baker’s yeast as a model organism, we document the resistance mechanism of a mutant lacking the arrestin gene ROD1, known to regulate nutrient transporter endocytosis. First, we show that 2DG triggers the endocytosis of many nutrient transporters. Mechanistically, 2DG leads to a transient inhibition of the AMPK signaling pathway, which in turn promotes the activation of Rod1, a pre-requisite for 2DG-induced endocytosis. Consequently, cells lacking Rod1 maintain various proteins at the plasma membrane including hexose transporters, the latter being essential for 2DG resistance. Hexose transporter stabilization at the cell surface may sustain glucose import and help cells cope with the 2DG-induced metabolic blockade, while also allowing 2DG detoxication.
Regulation of EBNA1 Protein Stability by PLOD1 Lysine Hydroxylase
Authors: Dheekollu Jayaraju , Wiedmer Andreas , Soldan Samantha S. , Castro Muñoz Leonardo Josué , Tang Hsin-Yao , Speicher David W. , Lieberman Paul M. 
Published: March 2022

AbstractEpstein-Barr virus (EBV) is a ubiquitous human γ-herpesvirus that is causally associated with various malignancies and autoimmune disease. Epstein-Barr Nuclear Antigen 1 (EBNA1) is the viral-encoded DNA binding protein required for viral episome maintenance and DNA replication during latent infection in proliferating cells. EBNA1 is known to be a highly stable protein, but its mechanism of protein stability is not completely understood. Proteomic analysis of EBNA1 revealed interaction with Procollagen Lysine-2 Oxoglutarate 5 Dioxygenase (PLOD) family of proteins. Depletion of PLOD1 by shRNA or inhibition with small molecule inhibitors 2,-2’ dipyridyl resulted in the loss of EBNA1 protein levels, along with a selective growth inhibition of EBV-positive lymphoid cells. PLOD1 depletion also caused a loss of EBV episomes from latently infected cells and inhibited oriP-dependent DNA replication. We used mass spectrometry to identify EBNA1 peptides with lysine hydroxylation at K460 or K461. Mutation of K460 to alanine or arginine abrogates EBNA1-driven DNA replication of oriP, while K461 mutations enhanced replication. These findings suggest that PLOD1 is a novel post-translational regulator of EBNA1 protein stability and function in viral plasmid replication, episome maintenance and host cell survival.ImportanceEBNA1 is essential for EBV latent infection and implicated in viral pathogenesis. We found that EBNA1 interacts with PLOD family of lysine hydroxylases and that this interaction is required for EBNA1 protein stability and function in viral persistence during viral latent infection. Identification of PLOD1 regulation of EBNA1 protein stability provide new opportunity to target EBNA1 for degradation in EBV associated disease.
Quantifying the capacity for assisted migration to achieve conservation and forestry goals under climate change
Authors: Zou Yibiao , Backus Gregory A. , Safford Hugh D. , Sawyer Sarah , Baskett Marissa L. 
Published: March 2022

AbstractMany tree species might be threatened with extinction because they cannot disperse or adapt quickly enough to keep pace with climate change. One potential, and potentially risky, strategy to mitigate this threat is assisted migration, the intentional movement of species to facilitate population range shifts to more climatically suitable locations under climate change. The ability for assisted migration to minimize risk and maximize conservation and forestry outcomes depends on a multi-faceted decision process for determining, what, where, and how much to move. To quantify how the benefits and risks of assisted migration could affect the decision-making process, we used a dynamical vegetation model parameterized with 23 tree species in the western United States. We found that most of the modeled species are likely to experience a substantial decline in biomass, potentially facing regional extinction by 2100 under the high-emission SSP5-85 climate-change scenario. Though simulations show assisted migration had little effect on the forestry goal of total biomass across all species, its effects on the conservation goal of promoting individual species’ persistence were far more substantial. Among eight assisted migration strategies we tested that differ in terms of life cycle stage of movement and target destination selection criteria, the approach that conserved the highest biomass for individual species involved relocating target seedlings to areas with the highest canopy openness. Although this strategy significantly reduced extinction risk for six at-risk species compared to no action, it also slightly reduced biomass of four species, due to increasing competition. Species with relatively weak tolerance to drought, fire or high temperature were the most likely candidate groups for assisted migration. This model framework could be applied to other forest ecosystems to evaluate the efficacy of assisted migration globally.
spongEffects: ceRNA modules offer patient-specific insights into the miRNA regulatory landscape
Authors: Boniolo Fabio , Hoffmann Markus , Roggendorf Norman , Tercan Bahar , Baumbach Jan , Castro Mauro A. A. , Robertson A. Gordon , Saur Dieter , List Markus 
Published: March 2022

ABSTRACTMotivationCancer is one of the leading causes of death worldwide. Despite significant improvements in prevention and treatment, mortality remains high for many cancer types. Hence, innovative methods that use molecular data to stratify patients and identify biomarkers are needed. Promising biomarkers can also be inferred from competing endogenous RNA (ceRNA) networks that capture the gene-miRNA gene regulatory landscape. Thus far, the role of these biomarkers could only be studied globally but not in a sample-specific manner. To mitigate this, we introduce spongEffects, a novel method that infers subnetworks (or modules) from ceRNA networks and calculates patient- or sample-specific scores related to their regulatory activity.ResultsWe show how spongEffects can be used for downstream interpretation and machine learning tasks such as tumor classification and for identifying subtype-specific regulatory interactions. In a concrete example of breast cancer subtype classification, we prioritize modules impacting the biology of the different subtypes. In summary, spongEffects prioritizes ceRNA modules as biomarkers and offers insights into the miRNA regulatory landscape. Notably, these module scores can be inferred from gene expression data alone and can thus be applied to cohorts where miRNA expression information is lacking.Availabilityhttps://bioconductor.org/packages/devel/bioc/html/SPONGE.htmlContactmarkus.daniel.hoffmann@tum.de;markus.list@tum.deSupplementary informationSupplementary data are available at Bioinformatics online.
Tuberculosis treatment failure associated with evolution of antibiotic resilience
Authors: Liu Qingyun , Zhu Junhao , Dulberger Charles L. , Stanley Sydney , Wilson Sean , Chung Eun Seon , Wang Xin , Culviner Peter , Liu Yue J. , Hicks Nathan D. , Babunovic Gregory H. , Giffen Samantha R. , Aldridge Bree B. , Garner Ethan C. , Rubin Eric J. , Chao Michael C. , Fortune Sarah M. 
Published: March 2022

AbstractAntibiotics are a cornerstone of medicine, placing bacterial pathogens under intense pressure to evolve new survival mechanisms. Analysis of 51,229 Mycobacterium tuberculosis (Mtb) clinical isolates identified an essential transcriptional regulator, Rv1830 (here named resR) as a frequent target of positive (adaptive) selection. resR mutants do not demonstrate canonical drug resistance or drug tolerance but instead have significantly faster recovery after drug treatment across all antibiotics and combinations tested, a phenotype which we term antibiotic resilience. ResR acts in a regulatory cascade with other growth-controlling transcriptional regulators WhiB2 and WhiA, which are also under positive selection in Mtb clinical isolates. Mutations of these genes are associated with treatment failure and the acquisition of canonical drug resistance.
Driving Forces underlying Selectivity Filter Gating in the MthK Potassium Channel
Authors: Kopec Wojciech , Thomson Andrew S. , de Groot Bert L. , Rothberg Brad S. 
Published: March 2022

ABSTRACTK+channel activity can be limited by C-type inactivation, which is likely initiated in part by dissociation of K+ions from the selectivity filter, and modulated by side chains surrounding the selectivity filter. Whereas crystallographic and computational studies have linked inactivation to a ‘collapsed’ selectivity filter conformation in the KcsA channel, the structural basis for selectivity filter gating in other K+channels has been less clear. Here, we combined electrophysiological recordings with molecular dynamics based,in silicoelectrophysiology simulations, to study selectivity filter gating in the model potassium channel MthK and its V55E mutant (analogous to KcsA E71) in the pore-helix. Experimentally, we find that MthK V55E has a lower open probability than the WT channel, due to decreased stability of the open state, as well as a lower unitary conductance. Simulations account for both aspects of these observations on the atomistic scale, showing that ion permeation in V55E is altered by two distinct orientations of the E55 side chain. In the ‘vertical’ orientation of E55, in which E55 forms a hydrogen bond with D64 (as observed with KcsA WT channels), the filter displays reduced conductance compared to MthK WT. In contrast, with ‘horizontal’ orientation, K+conductance is closer to MthK WT; however the selectivity filter stability in the conducting conformation is lowered, and the filter more readily transitions to the inactivated conformation. Surprisingly, these transitions of MthK WT and V55E channels to the non-conducting (inactivated) state observed in simulations are associated with a widening selectivity filter, unlike its narrowing seen in KcsA, and reminisce the recent structures of stably-inactivated, voltage-gated potassium channels:ShakerW434F and Kv1.2 W362F mutants, as well as WT Kv1.3 channels.
Mesoscopic oblique plane microscopy (Meso-OPM) with a diffractive light sheet- enabling large-scale 4D cellular resolution imaging
Authors: Shao Wenjun , Chang Minzi , Emmerich Kevin , Kanold Patrick O , Mumm Jeff S , Yi Ji 
Published: March 2022

AbstractFundamental understanding of large-scale dynamic connectivity within a living organism requires volumetric imaging over a large field of view (FOV) at biologically relevant speed and resolution. However, most microscopy methods make trade-offs between FOV and depth resolution, making it challenging to observe highly dynamic processes at cellular resolution in 3D across mesoscopic scales (e.g., whole zebrafish larva). To overcome this limitation, we have developed mesoscopic oblique plane microscopy (Meso-OPM) with a diffractive light sheet. By augmenting the illumination angle of the light sheet with a transmission grating, the axial resolution was improved ~6-fold over existing methods and ~2-fold beyond the diffraction limitation of the primary objective lens. We demonstrated an unprecedented FOV up to 5.4 × 3.3 mm with resolution of 2.5× 3 × 6 μm, allowing volumetric imaging of 3D cellular structures with a single scan. Applying Meso-OPM for in vivo imaging of zebrafish larvae, we report here the first in toto whole body volumetric recordings of neuronal activity at 2 Hz volume rate and the first example of whole body volumetric recordings of blood flow dynamics at 5 Hz with 3D cellular resolution.
A multidisciplinary analysis of the as-isolated Escherichia coli SufBC2D complex reveals the presence of two new iron-sulfur clusters
Authors: Veronesi Giulia , Pérard Julien , Clémancey Martin , Gerez Catherine , Duverger Yohann , Kieffer Isabelle , Barras Frédéric , Gambarelli Serge , Blondin Geneviève , de Choudens Sandrine Ollagnier 
Published: March 2022

ABSTRACTIron-sulfur (Fe-S) clusters are essential inorganic cofactors dedicated to a wide range of biological functions including electron transfer and catalysis. Specialized multi-protein machineries present in all types of organisms support their biosynthesis. These machineries encompass a scaffold protein on which Fe-S clusters are assembled before being transferred to cellular targets. Here, we describe the first characterization of the native Fe-S cluster of the anaerobically purified SufBC2D scaffold from Escherichia coli by XAS, Mössbauer, UV-visible absorption and EPR spectroscopy. Interestingly, we propose that SufBC2D harbors two types of Fe-S cluster, a [2Fe-2S] cluster with an unprecedented usual coordination and a previously unreported [3Fe-3S] cluster. These data combined with mutagenesis and biochemistry allow to propose ligands for these clusters. These results support the hypothesis that both SufB and SufD are involved in Fe-S cluster ligation and are discussed in the context of Fe-S cluster biogenesis where both [2Fe-2S] and [4Fe-4S] clusters need to mature cellular Fe-S protein targets.
Focal Non-invasive Deep-brain Stimulation with Temporal Interference for the Suppression of Epileptic Biomarkers
Authors: Acerbo Emma , Jegou Aude , Luff Charlotte , Dzialecka Patrycja , Botzanowski Boris , Missey Florian , Ngom Ibrahima , Lagarde Stanislas , Bartolomei Fabrice , Cassara Antonino , Neufeld Esra , Jirsa Viktor , Carron Romain , Grossman Nir , Williamson Adam 
Published: March 2022

AbstractNeurostimulation applied from deep brain stimulation (DBS) electrodes is an effective therapeutic intervention in patients suffering from intractable drug-resistant epilepsy when resective surgery is contraindicated or failed. Inhibitory DBS to suppress seizures and associated epileptogenic biomarkers could be performed with high-frequency stimulation (HFS), typically between 100 –165Hz, to various deep-seated targets such as for instance the Mesio-temporal lobe (MTL) which leads to changes in brain rhythms, specifically in the hippocampus. The most prominent alterations concern high-frequency oscillations (HFOs), namely increase in ripples, a reduction in pathological Fast Ripples (FRs), and a decrease in pathological interictal epileptiform discharges (IEDs). In the current study, we use Temporal Interference stimulation to provide a non-invasive focal DBS (130 Hz) of the MTL, specifically the hippocampus, which increases physiological ripples, and decreases the number of FRs and IEDs in a mouse model of epilepsy. Similarly, we show the inability of 130 Hz transcranial current stimulation (TCS) to achieve similar results. The method could potentially revolutionize how DBS, certainly in epilepsy, is performed, and we therefore further demonstrate the translatability to human subjects via measurements of the TI stimulation vs TCS in human cadavers. Results show the better penetration of TI fields into the human hippocampus as compared with TCS. Finally, we provide evidence of the efficacy of the specific form of Pulse-width Modulated TI (PWM-TI), implemented with square waves, which is used in this study.One Sentence SummaryA non-invasive deep brain stimulation applied via temporal interference achieves the suppression of biomarkers of epilepsy in mice and is scaled to humans.
Immune chromatin reader SP140 regulates microbiota and risk for inflammatory bowel disease
Authors: Fraschilla Isabella , Amatullah Hajera , Rahman Raza-Ur , Jeffrey Kate L. 
Published: March 2022

AbstractInflammatory bowel disease (IBD) is driven by host genetics and environmental factors, including commensal microorganisms. Epigenetics facilitate integration of environmental cues for transcriptional output. However, evidence of epigenetic dysregulation directly causing host-commensal dysbiosis and IBD is lacking. Speckled Protein 140 (SP140) is an immune-restricted chromatin ‘reader’ with homology to Autoimmune Regulator (AIRE). SP140 mutations associate with three immune diseases: Crohn’s disease (CD), multiple sclerosis (MS) and chronic lymphocytic leukemia (CLL), but disease-causing mechanisms remain undefined. Here we identify a critical immune-intrinsic role for SP140 in preventing expansion of inflammatory Proteobacteria, including Helicobacter in mice and Enterobacteriaceae in humans. Mice harboring altered microbiota due to hematopoietic Sp140 deficiency exhibited severe colitis which was transmissible upon co-housing and ameliorated with antibiotics. SP140 was critical for calibration of macrophage microbicidal responses required for normal host-commensal crosstalk and elimination of invasive pathogens. Mutations within this epigenetic reader may constitute a predisposing event in human diseases provoked by the microbiome, such as IBD and MS.
3’UTR-directed, kinase proximal mRNA decay inhibits C/EBPβ phosphorylation/activation to suppress senescence in tumor cells
Authors: Salotti Jacqueline , Asif Nida , Basu Srikanta , Das Aniruddha , Yang Mei , Karim Baktiar , Saylor Karen , Martin Nancy , Scheiblin David A. , Misra Sweta , Luke Brian T. , Andresson Thorkell , Lockett Stephen , Tessarollo Lino , Johnson Peter F. 
Published: March 2022

AbstractC/EBPβ is a potent regulator of oncogene-induced senescence (OIS) and the SASP. C/EBPβ is post-translationally activated in OIS cells by the effector kinases ERK1/2 and CK2. However, in tumor cells C/EBPβ activation is suppressed by its 3’UTR. 3′UTR regulation of protein activity (UPA) requires a G/U-rich element (GRE) and its cognate binding protein, HuR. These components segregateCEBPBtranscripts away from a perinuclear compartment harboring ERK1/2 and CK2, restricting C/EBPβ from its activating kinases. We report here that the mRNA decay proteins UPF1 and Staufen1/2 are essential UPA factors enriched within the perinuclear cytoplasm. STAU1/2 and UPF1 overlap with CK2 on perinuclear signaling endosomes where they promote localizedCEBPBmRNA decay. UPF1 or STAU1/2 depletion in tumor cells increasedCEBPBtranscripts adjacent to CK2 foci, coinciding with C/EBPβ activation and senescence. The GRE and an adjacent STAU binding site independently suppress C/EBPβ-mediated senescence, while a distinct 3’UTR region inhibits its SASP-inducing activity.KrasG12D-driven lung tumors in mice carrying aCebpbGRE deletion rarely progressed to malignant adenocarcinomas, demonstrating the importance of UPA to enable tumor progressionin vivo. Thus, kinase-proximal mRNA decay is a novel mechanism that inhibits C/EBPβ activation in tumor cells to facilitate senescence bypass.
Holobiont transcriptomes for the critically endangered staghorn coral (Acropora cervicornis) from two environmentally distinct sites on Turneffe Atoll, Belize
Authors: Lesneski Kathryn C. , Labadorf Adam T , Lord Karina Scavo , Agus Filisia , Finnerty John R. 
Published: March 2022

AbstractHistorically, staghorn coral (Acropora cervicornis) was a preeminent reef-builder in the Caribbean and Tropical Western Atlantic, where it constructed extensive thickets at 5-20 m depth that supported diverse ecosystems and provided coastal populations with food, storm protection, and income from tourism. In recent decades, A. cervicornis declined precipitously, up to 97% in some localities. To reverse its decline, widespread efforts are underway to characterize the phenotypic and genetic diversity of persisting populations with the goal of restoring them to historical levels by out-planting nursery grown specimens. To support this target, we developed transcriptomes for two A. cervicornis populations located in Turneffe Atoll Marine Reserve, Belize. These populations experience significantly different temperatures, light levels and water currents, and they harbor individuals that differ in key phenotypes. Because differentiating the gene activity of diverse taxa—i.e., coral host, algal photosymbiont, plus associated eukaryotes, bacteria, archaea, and viruses— is critical to understanding the function of the coral holobiont, we developed a pipeline for parsing transcripts by taxon. Separate transcriptomes for each population contain complete representatives for >96% of 978 conserved metazoan single copy orthologs. The taxonomic breakdown of transcripts differed between sites, with more bacterial transcripts recovered from Calabash Caye and more symbiont transcripts from Blackbird Caye. The assembled transcriptomes will facilitate gene expression studies and in silico cloning from this endangered coral.
The growth rate of DNA condensate droplets increases with the size of participating subunits
Authors: Agarwal Siddharth , Osmanovic Dino , Klocke Melissa A. , Franco Elisa 
Published: March 2022

AbstractLiquid–liquid phase separation (LLPS) is a common phenomenon underlying the formation of dynamic membraneless organelles in biological cells, which are emerging as major players in controlling cellular functions and health. The bottom-up synthesis of biomolecular liquid systems with simple constituents, like nucleic acids and peptides, is useful to understand LLPS in nature as well as to develop programmable means to build new amorphous materials with properties matching or surpassing those observed in natural condensates. In particular, understanding which parameters determine condensate growth kinetics is essential for the synthesis of condensates with the capacity for active, dynamic behaviors. Here we use DNA nanotechnology to study artificial liquid condensates through programmable star-shaped subunits, focusing on the effects of changing subunit size. First, we show that LLPS is achieved in a six-fold range of subunit size. Second, we demonstrate that the rate of growth of condensate droplets scales with subunit size. Our investigation is supported by a general model that describes how coarsening and coalescence are expected to scale with subunit size under ideal assumptions. Beyond suggesting a route toward achieving control of LLPS kinetics via design of subunit size in synthetic liquids, our work suggests that particle size may be a key parameter in biological condensation processes.