bluuebunny/crossref_metadata_2025_split huggingface dataset:
Nutrient Responsive O-GlcNAcylation Dynamically Modulates Galectin 3 Secretion
Authors: Mathew Mohit P. , Donaldson Julie G. , Hanover John A. 
Published: April 2021

ABSTRACTEndomembrane glycosylation and cytoplasmic O-GlcNAcylation each play essential roles in nutrient sensing, and in fact, characteristic changes in glycan patterns have been described in disease states such as diabetes and cancer. These changes in glycosylation have important functional roles and can drive disease progression. However, little is known about the molecular mechanisms underlying how these signals are integrated and transduced into biological effects. Galectins are proteins that bind glycans that are secreted by a poorly characterized non-classical secretory mechanism. Once outside the cell, galectins bind to terminal galactose residues of cell surface glycans and modulate numerous extracellular functions like clathrin independent endocytosis (CIE). Originating in the cytoplasm, galectins are predicted substrates for O-GlcNAc addition and removal. This study shows that galectin 3 is O-GlcNAcylated, and that changes in O-GlcNAc cycling alters its secretion. Moreover, we determined that there is a significant difference in O-GlcNAcylation status between cytoplasmic and secreted galectin 3. We observed dramatic alterations in galectin 3 secretion in response to nutrient conditions and that these changes were dependent on dynamic O-GlcNAcylation. Finally, we showed that alterations in galectin 3 secretion via disrupted O-GlcNAcylation drove changes in CIE. These results indicate that dynamic O-GlcNAcylation of galectin 3 plays a role in modulating its secretion and can tune its function of transducing nutrient sensing information coded in cell surface glycosylation into biological effects.
Biochemical alterations precede neurobehavioral deficits in a novel mouse model of Friedreich ataxia
Authors: Medina-Carbonero Marta , Sanz-Alcázar Arabela , Britti Elena , Delaspre Fabien , Cabiscol Elisa , Ros Joaquim , Tamarit Jordi 
Published: April 2021

ABSTRACTFriedreich Ataxia (FA) is a rare neuro-cardiodegenerative disease, caused by partial deficiency of frataxin, a mitochondrial protein. This deficiency is caused by the presence of a GAA triplet expansion in the first intron of the frataxin gene or, in some patients, by point mutations. Generating mouse models mimicking FA has been challenging, as this disease is manifested when frataxin levels are below a pathological threshold. In the present work, we have characterized a new mouse model of FA (FXNI151F) based on a pathological point mutation (I154F) present in some FA patients. These mice present very low frataxin levels in all tissues and display neurological deficits resembling those observed in FA patients. We have also observed decreased content of components from OXPHOS complexes I and II, decreased aconitase activity, and alterations in the antioxidant defenses. Remarkably, these biochemical alterations precede the appearance of neurological symptoms and present a different profile in heart and brain or cerebellum. The FXNI151Fmouse is an excellent tool for analyzing the consequences of frataxin deficiency in different tissues and for testing new therapies.
Brassica rapadomestication: untangling wild and feral forms and convergence of crop morphotypes
Authors: McAlvay Alex C. , Ragsdale Aaron P. , Mabry Makenzie E. , Qi Xinshuai , Bird Kevin A. , Velasco Pablo , An Hong , Pires J. Chris , Emshwiller Eve 
Published: April 2021

AbstractThe study of domestication contributes to our knowledge of evolution and crop genetic resources. Human selection has shaped wildBrassica rapainto diverse turnip, leafy, and oilseed crops. Despite its worldwide economic importance and potential as a model for understanding diversification under domestication, insights into the number of domestication events and initial crop(s) domesticated inB. rapahave been limited due to a lack of clarity about the wild or feral status of conspecific non-crop relatives. To address this gap and reconstruct the domestication history ofB. rapa, we analyzed 68,468 genotyping-by-sequencing-derived SNPs for 416 samples in the largest diversity panel of domesticated and weedyB. rapato date. To further understand the center of origin, we modeled the potential range of wildB. rapaduring the mid-Holocene. Our analyses of genetic diversity acrossB. rapamorphotypes suggest that non-crop samples from the Caucasus, Siberia, and Italy may be truly wild, while those occurring in the Americas and much of Europe are feral. Clustering, tree-based analyses, and parameterized demographic inference further indicate that turnips were likely the first crop type domesticated, from which leafy types in East Asia and Europe were selected from distinct lineages. These findings clarify the domestication history and nature of wild crop genetic resources forB. rapa, which provides the first step toward investigating cases of possible parallel selection, the domestication and feralization syndrome, and novel germplasm forBrassicacrop improvement.
Dynamic task-belief is an integral part of decision-making
Authors: Xue Cheng , Kramer Lily E. , Cohen Marlene R. 
Published: April 2021

SummaryNatural decisions involve two seemingly separable processes: inferring the relevant task (task-belief) and performing the believed-relevant task. The assumed separability has led to the traditional practice of studying task-switching and perceptual decision-making individually. Here, we used a novel paradigm to manipulate and measure macaque monkeys’ task-belief, and demonstrated inextricable neuronal links between flexible task-belief and perceptual decision-making. We showed that in animals, but not artificial networks that performed as well or better than the animals, stronger task-belief is associated with better perception. Correspondingly, recordings from neuronal populations in cortical areas 7a and V1 revealed that stronger task-belief is associated with better discriminability of the believed-relevant but not the believed-irrelevant feature. Perception also impacts belief updating: noise fluctuations in V1 help explain how task-belief is updated. Our results demonstrate that complex tasks and multi-area recordings can reveal fundamentally new principles of how biology affects behavior in health and disease.
The chaperone Tsr2 regulates Rps26 release and reincorporation from mature ribosomes to enable a reversible, ribosome-mediated response to stress
Authors: Yang Yoon-Mo , Karbstein Katrin 
Published: April 2021

SummaryAlthough ribosome assembly is quality controlled to maintain protein homeostasis, different ribosome populations have been described. How these form, especially under stress conditions that impact energy levels and stop the energy-intensive production of ribosomes, remains unknown. Here we demonstrate how a physiologically relevant ribosome population arises during high Na+and pH stress via dissociation of Rps26 from fully assembled ribosomes to enable a translational response to these stresses. The chaperone Tsr2 releases Rps26 in the presence of high Na or pHin vitroand is required for Rps26 releasein vivo. Moreover, Tsr2 stores free Rps26 and promotes re-incorporation of the protein, thereby repairing the subunit after the stress subsides. Our data implicate a residue in Rps26 involved in Diamond Blackfan Anemia in mediating the effects of Na+. These data demonstrate how different ribosome populations can arise rapidly, without major energy input, and without bypass of quality control mechanisms.Graphical AbstractHighlightsTsr2 releases Rps26 from mature ribosomes to remodel ribosome populationsTsr2 stores released Rps26 and allows for ribosome repair after stressRps26 exploits a Mg binding site linked to Diamond Blackfan Anemia (DBA)Chaperone-mediated ribosome remodeling might be common for chaperoned RPs
An Autoantigen-ome from HS-Sultan B-Lymphoblasts Offers a Molecular Map for Investigating Autoimmune Sequelae of COVID-19
Authors: Wang Julia Y. , Zhang Wei , Roehrl Victor B. , Roehrl Michael W. , Roehrl Michael H. 
Published: April 2021

AbstractTo understand how COVID-19 may induce autoimmune diseases, we have been compiling an atlas of COVID-autoantigens (autoAgs). Using dermatan sulfate (DS) affinity enrichment of autoantigenic proteins extracted from HS-Sultan lymphoblasts, we identified 362 DS-affinity proteins, of which at least 201 (56%) are confirmed autoAgs. Comparison with available multi-omic COVID data shows that 315 (87%) of the 362 proteins are affected in SARS-CoV-2 infection via altered expression, interaction with viral components, or modification by phosphorylation or ubiquitination, at least 186 (59%) of which are known autoAgs. These proteins are associated with gene expression, mRNA processing, mRNA splicing, translation, protein folding, vesicles, and chromosome organization. Numerous nuclear autoAgs were identified, including both classical ANAs and ENAs of systemic autoimmune diseases and unique autoAgs involved in the DNA replication fork, mitotic cell cycle, or telomerase maintenance. We also identified many uncommon autoAgs involved in nucleic acid and peptide biosynthesis and nucleocytoplasmic transport, such as aminoacyl-tRNA synthetases. In addition, this study found autoAgs that potentially interact with multiple SARS-CoV-2 Nsp and Orf components, including CCT/TriC chaperonin, insulin degrading enzyme, platelet-activating factor acetylhydrolase, and the ezrin-moesin-radixin family. Furthermore, B-cell-specific IgM-associated ER complex (including MBZ1, BiP, heat shock proteins, and protein disulfide-isomerases) is enriched by DS-affinity and up-regulated in B-cells of COVID-19 patients, and a similar IgH-associated ER complex was also identified in autoreactive pre-B1 cells in our previous study, which suggests a role of autoreactive B1 cells in COVID-19 that merits further investigation. In summary, this study demonstrates that virally infected cells are characterized by alterations of proteins with propensity to become autoAgs, thereby providing a possible explanation for infection-induced autoimmunity. The COVID autoantigen-ome provides a valuable molecular resource and map for investigation of COVID-related autoimmune sequelae and considerations for vaccine design.
Decreasing Mitochondrial RNA Polymerase Activity Reverses Biased Inheritance of Hypersuppressive mtDNA
Authors: Corbi Daniel , Amon Angelika 
Published: April 2021

AbstractFaithful inheritance of mitochondrial DNA (mtDNA) is crucial for cellular respiration/oxidative phosphorylation and mitochondrial membrane potential. However, how mtDNA is transmitted to progeny is not fully understood. We utilized hypersuppressive mtDNA, a class of respiratory deficientSaccharomyces cerevisiaemtDNA that is preferentially inherited over wild-type mtDNA (rho+), to uncover the factors governing mtDNA inheritance. We found that regions ofrho+mtDNA persisted after hypersuppressive takeover indicating that hypersuppressive preferential inheritance may partially be due to active destruction ofrho+mtDNA. From a multicopy suppression screen, we found that overexpression of putative mitochondrial RNA exonucleasePET127reduced hypersuppressive biased inheritance. This suppression requiredPET127binding to the mitochondrial RNA polymeraseRPO41but notPET127exonuclease activity. A temperature-sensitive allele ofRPO41improvedrho+mtDNA inheritance relative to hypersuppressive mtDNA at semi-permissive temperatures revealing a previously unknown role forrho+transcription in promoting hypersuppressive mtDNA inheritance.
The neuroprotective effect of meloxicam in a transient ischemia model involves an increase in axonal sprouting but a decrease in new neuron formation after 7 days of reperfusion
Authors: Ugidos IF , González-Rodríguez P , Santos-Galdiano M , Font-Belmonte E , Anuncibay-Soto B , Pérez-Rodríguez D , Fernández-López A 
Published: April 2021

AbstractThe inflammatory response plays an important role in neuroprotection and regeneration after ischemic insult. The use of non-steroidal anti-inflammatory drugs has been a matter of debate as to whether they have beneficial or detrimental effects. In this context, the effects of the anti-inflammatory agent meloxicam have been scarcely documented after stroke, but its ability to inhibit both cyclooxygenase isoforms (1 and 2) could be a promising strategy to modulate post-ischemic inflammation. This study analyzed the effect of the anti-inflammatory agent meloxicam in a transient focal ischemia model in rats, measuring its neuroprotective effect after 48 hours and 7 days of reperfusion and the effects of the treatment on the glial scar and regenerative events such as the generation of new progenitors in the subventricular zone and axonal sprouting at the edge of the damaged area. We show that meloxicam’s neuroprotective effects remained after 7 days of reperfusion even if its administration was restricted to the two first days after ischemia. Moreover, meloxicam treatment modulated glial scar reactivity, which matched with an increase in axonal sprouting. However, this treatment decreased the formation of neuronal progenitor cells. This study discusses the dual role of anti-inflammatory treatments after stroke and encourages the careful analysis of both the neuroprotective and the regenerative effects in preclinical studies.Abstract Figure
Soil, ocean, hot spring, and host-associated environments reveal unique selection pressures on genomic features of bacteria in microbial communities
Authors: Chuckran Peter F. , Hungate Bruce , Schwartz Egbert , Dijkstra Paul 
Published: April 2021

ABSTRACTFree-living bacteria in nutrient limited environments often exhibit small genomes which curb the cost of reproduction – a phenomenon known as genomic streamlining. Streamlining has been associated with a suite of traits such as reduced GC content, fewer 16S rRNA copies, and a lower abundance of regulatory genes, such as sigma (σ) factors. Here, we analyzed these traits from 116 publicly available metagenomes derived from marine, soil, host associated, and thermophilic communities. In marine and thermophilic communities, genome size and GC content declined in parallel, but GC content was higher in thermophilic communities. In soils, the relationship between genome size and GC content was negative, suggesting a different selection pressure on genome size and GC content in soil bacteria. The abundance of σ-factors varied with average genome size, ecosystem type, and the specific functions regulated by the sigma factor. In marine environments, housekeeping and heat-shock σ-factor genes (rpoDandrpoHrespectively) increased as genome size declined, and σ-factor responsible for flagella biosynthesis (fliA) decreased, suggesting a trade-off between nutrient conservation and chemotaxis. In soils, a high abundance offliAand the stress response σ-factor gene (rpoS) was associated with smaller average genome size and often located in harsh and/or carbon-limited environments such as deserts or agricultural fields – suggesting an increased capacity for stress response and mobility in nutrient-poor soils. This work showcases how ecosystem-specific environmental constraints force trade-offs which are then embedded in the genomic features of bacteria in microbial communities, specifically genome size, GC content, and regulatory genes, and further highlights the importance of considering these features in microbial community analysis.
Defined diets for freshwater planarians
Authors: Abel Chris , Powers Kaleigh , Gurung Gargi , Pellettieri Jason 
Published: April 2021

ABSTRACTPlanarian flatworms are popular invertebrate models for basic research on stem cell biology and regeneration. These animals are commonly maintained on a diet of homogenized calf liver or boiled egg yolk in the laboratory, introducing a source of uncontrolled experimental variability. Here, we report the development of defined diets, prepared entirely from standardized, commercially sourced ingredients, for the freshwater speciesSchmidtea mediterranea, Dugesia japonica, andGirardia dorotocephala. These food sources provide an opportunity to test the effects of specific nutritional variables on biological phenomena of interest. Defined diet consumption was not sufficient for growth and only partially induced the increase in stem cell division that normally accompanies feeding, suggesting these responses are not solely determined by caloric intake. While our defined diet formulations do not support long-term planarian maintenance, they do enable delivery of double-stranded RNA for gene knockdown in a manner that provides unique advantages in some experimental contexts. We also present a new approach for preserving tissue integrity during hydrogen peroxide bleaching of liver-fed animals. These tools will empower research on the connections between diet, metabolism, and stem cell biology in the experimentally tractable planarian system.
Exploration of synergistic action of cell wall-degrading enzymes againstMycobacterium tuberculosis
Authors: van Schie Loes , Borgers Katlyn , Michielsen Gitte , Plets Evelyn , Vuylsteke Marnik , Tiels Petra , Festjens Nele , Callewaert Nico 
Published: April 2021

SynopsisBackgroundThe major global health threat tuberculosis is caused byMycobacterium tuberculosis(Mtb). Mtb has a complex cell envelope – a partially covalently linked composite of polysaccharides, peptidoglycan and lipids, including a mycolic acid layer – which conveys pathogenicity but also protects against antibiotics. Given previous successes in treating gram-positive and -negative infections with cell wall degrading enzymes, we investigated such approach for Mtb.Objectives(i) Development of an Mtb microtiter growth inhibition assay that allows undisturbed cell envelope formation, to overcome the invalidation of results by typical clumped Mtb-growth in surfactant-free assays. (ii) Exploring anti-Mtb potency of cell wall layer-degrading enzymes. (iii) Investigation of the concerted action of several such enzymes.MethodsWe inserted a bacterial luciferase-operon in an auxotrophic Mtb strain to develop a microtiter assay that allows proper evaluation of cell wall degrading anti-Mtb enzymes. We assessed growth-inhibition by enzymes (recombinant mycobacteriophage mycolic acid esterase (LysB), fungal α-amylase and human and chicken egg white lysozymes) and combinations thereof, in presence or absence of biopharmaceutically acceptable surfactant.ResultsOur biosafety level-2 assay identified both LysB and lysozymes as potent Mtb-inhibitors, but only in presence of surfactant. Moreover, most potent disruption of the mycolic acid hydrophobic barrier was obtained by the highly synergistic combination of LysB, α-amylase and polysorbate 80.ConclusionsSynergistically acting cell wall degrading enzymes are potently inhibiting Mtb – which sets the scene for the design of specifically tailored antimycobacterial (fusion) enzymes. Airway delivery of protein therapeutics has already been established and should be studied in animal models for active TB.
COVID-19 Time-varying Reproduction Numbers Worldwide: An Empirical Analysis of Mandatory and Voluntary Social Distancing
Authors: Chudik Alexander , Pesaran M. Hashem , Rebucci Alessandro 
Published: April 2021

AbstractThis paper estimates time-varying COVID-19 reproduction numbers worldwide solely based on the number of reported infected cases, allowing for under-reporting. Estimation is based on a moment condition that can be derived from an agent-based stochastic network model of COVID-19 transmission. The outcomes in terms of the reproduction number and the trajectory of per-capita cases through the end of 2020 are very diverse. The reproduction number depends on the transmission rate and the proportion of susceptible population, or the herd immunity effect. Changes in the transmission rate depend on changes in the behavior of the virus, re-flecting mutations and vaccinations, and changes in people’s behavior, reflecting voluntary or government mandated isolation. Over our sample period, neither mutation nor vaccination are major factors, so one can attribute variation in the transmission rate to variations in behavior. Evidence based on panel data models explaining transmission rates for nine European countries indicates that the diversity of outcomes resulted from the non-linear interaction of mandatory containment measures, voluntary precautionary isolation, and the economic incentives that gov-ernments provided to support isolation. These effects are precisely estimated and robust to various assumptions. As a result, countries with seemingly different social distancing policies achieved quite similar outcomes in terms of the reproduction number. These results imply that ignoring the voluntary component of social distancing could introduce an upward bias in the estimates of the effects of lock-downs and support policies on the transmission rates.JEL ClassificationD0, F6, C4, I120, E7
Advancing quality-control for NGS measurement of actionable mutations in circulating tumor DNA
Authors: Willey James C. , Morrison Tom , Austermiller Brad , Crawford Erin L. , Craig Daniel J. , Blomquist Thomas M. , Jones Wendell D. , Wali Aminah , Lococo Jennifer S. , Haseley Nathan , Richmond Todd A. , Novoradovskaya Natalia , Kusko Rebecca , Chen Guangchun , Li Quan-Zhen , Johann Don , Deveson Ira W. , Mercer Tim , Wu Leihong , Xu Joshua 
Published: April 2021

SUMMARYThe primary objective of the FDA-led Sequencing and Quality Control Phase 2 (SEQC2) project is to develop standard analysis protocols and quality control metrics for use in DNA testing to enhance scientific research and precision medicine. This study reports a targeted next generation sequencing (NGS) method that enables more accurate detection of actionable mutations in circulating tumor DNA (ctDNA) clinical specimens. This advancement was enabled by designing a synthetic internal standard spike-in for each actionable mutation target, suitable for use in NGS following hybrid-capture enrichment and unique molecular index (UMI) or non-UMI library preparation. When mixed with contrived ctDNA reference samples, internal standards enabled calculation of technical error rate, limit of blank, and limit of detection for each variant at each nucleotide position, in each sample. True positive mutations with variant allele fraction too low for detection by current practice were detected with this method, thereby increasing sensitivity.