bluuebunny/crossref_metadata_2025_split huggingface dataset:
Process controlling iron–manganese regulation of the Southern Ocean biological carbon pump
Authors: Anugerahanti Prima , Tagliabue Alessandro 
Published: May 2023

Iron (Fe) is a key limiting nutrient driving the biological carbon pump and is routinely represented in global ocean biogeochemical models. However, in the Southern Ocean, the potential role for other micronutrients has not received the same attention. For example, although manganese (Mn) is essential to photosynthetic oxygen production and combating oxidative stress, it is not included in ocean models and a clear understanding of its interaction with Fe in the region is lacking. This is especially important for the Southern Ocean because both Mn and Fe are strongly depleted. We use a hierarchical modelling approach to explore how the physiological traits associated with Fe and Mn contribute to driving the footprint of micronutrient stress across different phytoplankton functional types (PFTs). We find that PFT responses are driven by physiological traits associated with their physiological requirements and acclimation to environmental conditions. Southern Ocean-specific adaptations to prevailing low Fe, such as large photosynthetic antenna sizes, are of major significance for the regional biological carbon pump. Other traits more strongly linked to Mn, such as dealing with oxidative stress, may become more important under a changing Fe supply regime.
This article is part of a discussion meeting issue ‘Heat and carbon uptake in the Southern Ocean: the state of the art and future priorities’.
A clearer view of Southern Ocean air–sea interaction using surface heat flux asymmetry
Authors: Josey Simon A. , Grist Jeremy P. , Mecking Jennifer V. , Moat Ben I. , Schulz Eric 
Published: May 2023

Progress in understanding Southern Ocean heat exchange and wind forcing is discussed and new results presented. These include a metric of the zonal asymmetry between surface ocean heat gain in the Atlantic/Indian sector and heat loss in the Pacific sector. The asymmetry arises from an intersector variation in the humidity gradient between the sea surface and near-surface atmosphere. This gradient increases by 60% in the Pacific sector enabling a 20 Wm−2stronger latent heat loss compared with the Atlantic/Indian sector. The new metric is used for intercomparison of atmospheric reanalyses and CMIP6 climate simulations. CMIP6 has weaker Atlantic/Indian sector heat gain compared with the reanalyses primarily due to Indian Ocean sector differences. The potential for surface flux buoys to provide an observation-based counterpart to the asymmetry metric is explored. Over the past decade, flux buoys have been deployed at two sites (south of Tasmania and upstream of Drake Passage). The data record provided by these moorings is assessed and an argument developed for a third buoy to sample the Atlantic/Indian sector of the asymmetry metric. To close, we assess evidence that the main westerly wind belt has strengthened and moved southward in recent decades using the ERA5 reanalysis.This article is part of a discussion meeting issue 'Heat and carbon uptake in the Southern Ocean: the state of the art and future priorities'.
Finale: impact of the ORCHESTRA/ENCORE programmes on Southern Ocean heat and carbon understanding
Authors: Meijers Andrew J. S. , Meredith Michael P. , Shuckburgh Emily F. , Kent Elizabeth C. , Munday David R. , Firing Yvonne L. , King Brian , Smyth Tim J. , Leng Melanie J. , George Nurser A. J. , Hewitt Helene T. , Povl Abrahamsen E. , Weiss Alexandra , Yang Mingxi , Bell Thomas G. , Alexander Brearley J. , Boland Emma J. D. , Jones Daniel C. , Josey Simon A. , Owen Robyn P. , Grist Jeremy P. , Blaker Adam T. , Biri Stavroula , Yelland Margaret J. , Pimm Ciara , Zhou Shenjie , Harle James , Cornes Richard C. 
Published: May 2023

The 5-year Ocean Regulation of Climate by Heat and Carbon Sequestration and Transports (ORCHESTRA) programme and its 1-year extension ENCORE (ENCORE is the National Capability ORCHESTRA Extension) was an approximately 11-million-pound programme involving seven UK research centres that finished in March 2022. The project sought to radically improve our ability to measure, understand and predict the exchange, storage and export of heat and carbon by the Southern Ocean. It achieved this through a series of milestone observational campaigns in combination with model development and analysis. Twelve cruises in the Weddell Sea and South Atlantic were undertaken, along with mooring, glider and profiler deployments and aircraft missions, all contributing to measurements of internal ocean and air–sea heat and carbon fluxes. Numerous forward and adjoint numerical experiments were developed and supported by the analysis of coupled climate models. The programme has resulted in over 100 peer-reviewed publications to date as well as significant impacts on climate assessments and policy and science coordination groups. Here, we summarize the research highlights of the programme and assess the progress achieved by ORCHESTRA/ENCORE and the questions it raises for the future.This article is part of a discussion meeting issue ‘Heat and carbon uptake in the Southern Ocean: the state of the art and future priorities’.
Hypoxia-inducible factor induces cysteine dioxygenase and promotes cysteine homeostasis inCaenorhabditis elegans
Authors: Warnhoff Kurt , Bhattacharya Sushila , Snoozy Jennifer , Breen Peter C. , Ruvkun Gary 
Published: May 2023

AbstractDedicated genetic pathways regulate cysteine homeostasis. For example, high levels of cysteine activate cysteine dioxygenase, a key enzyme in cysteine catabolism in most animal and many fungal species. The mechanism by which cysteine dioxygenase is regulated is largely unknown. In an unbiased genetic screen for mutations that activate cysteine dioxygenase (cdo-1) in the nematodeC. elegans,we isolated loss-of-function mutations inrhy-1andegl-9,which encode proteins that negatively regulate the stability or activity of the oxygen-sensing hypoxia inducible transcription factor (hif-1). EGL-9 and HIF-1 are core members of the conserved eukaryotic hypoxia response. However, we demonstrate that the mechanism of HIF-1-mediated induction ofcdo-1is largely independent of EGL-9 prolyl hydroxylase activity and the von Hippel-Lindau E3 ubiquitin ligase, the classical hypoxia signaling pathway components. We demonstrate thatC. elegans cdo-1is transcriptionally activated by high levels of cysteine andhif-1.hif-1-dependent activation ofcdo-1occurs downstream of an H2S-sensing pathway that includesrhy-1, cysl-1,andegl-9. cdo-1transcription is primarily activated in the hypodermis where it is also sufficient to drive sulfur amino acid metabolism. Thus, the regulation ofcdo-1byhif-1reveals a negative feedback loop that maintains cysteine homeostasis. High levels of cysteine stimulate the production of an H2S signal. H2S then acts through therhy-1/cysl-1/egl-9signaling pathway to increase HIF-1-mediated transcription ofcdo-1,promoting degradation of cysteine via CDO-1.
Exchange between compartments regulates steady states and stochastic switching of a multisite phosphorylation network
Authors: Schmidt Hannah N. , Leopin Emily E. , Abel Steven M. 
Published: May 2023

AbstractThe phosphoregulation of proteins with multiple phosphorylation sites is governed by biochemical reaction networks that can exhibit multistable behavior. However, the behavior of such networks is typically studied in a single reaction volume, while cells are spatially organized into compartments that can exchange proteins. In this work, we use stochastic simulations to study the impact of compartmentalization on a two-site phosphorylation network. We characterize steady states and fluctuation-driven transitions between them as a function of the rate of protein exchange between two compartments. Surprisingly, the rate of stochastic switching between states depends nonmonotonically on the protein exchange rate, with the highest rate of switching occurring at intermediate exchange rates. At sufficiently small exchange rates, the state of the system and rate of switching are controlled largely by fluctuations in the balance of enzymes in each compartment. This leads to negatively correlated states in the compartments. For large exchange rates, the two compartments behave as a single effective compartment. However, when the compartmental volumes are unequal, the behavior differs from a single compartment with the same total volume. These results demonstrate that exchange of proteins between distinct compartments can regulate the emergent behavior of a common signaling motif.
Benchmarking splice variant prediction algorithms using massively parallel splicing assays
Authors: Smith Cathy , Kitzman Jacob O. 
Published: May 2023

AbstractBackgroundVariants that disrupt mRNA splicing account for a sizable fraction of the pathogenic burden in many genetic disorders, but identifying splice-disruptive variants (SDVs) beyond the essential splice site dinucleotides remains difficult. Computational predictors are often discordant, compounding the challenge of variant interpretation. Because they are primarily validated using clinical variant sets heavily biased to known canonical splice site mutations, it remains unclear how well their performance generalizes.ResultsWe benchmarked eight widely used splicing effect prediction algorithms, leveraging massively parallel splicing assays (MPSAs) as a source of experimentally determined ground-truth. MPSAs simultaneously assay many variants to nominate candidate SDVs. We compared experimentally measured splicing outcomes with bioinformatic predictions for 3,616 variants in five genes. Algorithms’ concordance with MPSA measurements, and with each other, was lower for exonic than intronic variants, underscoring the difficulty of identifying missense or synonymous SDVs. Deep learning-based predictors trained on gene model annotations achieved the best overall performance at distinguishing disruptive and neutral variants. Controlling for overall call rate genome-wide, SpliceAI and Pangolin also showed superior overall sensitivity for identifying SDVs. Finally, our results highlight two practical considerations when scoring variants genome-wide: finding an optimal score cutoff, and the substantial variability introduced by differences in gene model annotation, and we suggest strategies for optimal splice effect prediction in the face of these issues.ConclusionSpliceAI and Pangolin showed the best overall performance among predictors tested, however, improvements in splice effect prediction are still needed especially within exons.
Translation of non-canonical open reading frames as a cancer cell survival mechanism in childhood medulloblastoma
Authors: Hofman Damon A. , Ruiz-Orera Jorge , Yannuzzi Ian , Murugesan Rakesh , Brown Adam , Clauser Karl R. , Condurat Alexandra L. , van Dinter Jip T. , Engels Sem A.G. , Goodale Amy , van der Lugt Jasper , Abid Tanaz , Wang Li , Zhou Kevin N. , Vogelzang Jayne , Ligon Keith L. , Phoenix Timothy N. , Roth Jennifer A. , Root David E. , Hubner Norbert , Golub Todd R. , Bandopadhayay Pratiti , van Heesch Sebastiaan , Prensner John R. 
Published: May 2023

SummaryA hallmark of high-risk childhood medulloblastoma is the dysregulation of RNA translation. Currently, it is unknown whether medulloblastoma dysregulates the translation of putatively oncogenic non-canonical open reading frames. To address this question, we performed ribosome profiling of 32 medulloblastoma tissues and cell lines and observed widespread non-canonical ORF translation. We then developed a step-wise approach to employ multiple CRISPR-Cas9 screens to elucidate functional non-canonical ORFs implicated in medulloblastoma cell survival. We determined that multiple lncRNA-ORFs and upstream open reading frames (uORFs) exhibited selective functionality independent of the main coding sequence. One of these, ASNSD1-uORF or ASDURF, was upregulated, associated with the MYC family oncogenes, and was required for medulloblastoma cell survival through engagement with the prefoldin-like chaperone complex. Our findings underscore the fundamental importance of non-canonical ORF translation in medulloblastoma and provide a rationale to include these ORFs in future cancer genomics studies seeking to define new cancer targets.HighlightsRibo-seq reveals widespread translation of non-canonical ORFs in medulloblastomaHigh-resolution CRISPR tiling reveals uORF functions in medulloblastomaASNSD1-uORF controls downstream pathways with the prefoldin-like complexASNSD1-uORF is necessary for medulloblastoma cell survival
Legume-nodulating rhizobia are widespread in soils and plants across the island of O‘ahu, Hawai‘i
Authors: Abe Jonathan N. A. , Dhungana Ishwora , Nguyen Nhu H. 
Published: May 2023

AbstractLegumes and their interaction with rhizobia represent one of the most well-characterized symbioses that are widespread across both natural and agricultural environments. However, larger distribution patterns and host associations on isolated Pacific islands with many native and introduced hosts have not been well-documented. Here, we used molecular and culturing techniques to characterize rhizobia from soils and 24 native and introduced legume species on the island of O’ahu, Hawai’i. We chose two of these isolates to inoculated an endemic legume tree,Erythina sandwicensisto measure nodulation potentials and host benefits. We found that all rhizobia genera can be found in the soil, where onlyCupriaviduswas found at all sites, although at lower abundance relative to other more common genera such as Rhizobium (and close relatives),Bradyzhizobium, andDevosia. Bradyrhizobiumwas the most common nodulator of plants, where the strainBradyrhizobiumsp. strain JA1 is a generalist capable of forming nodules on nine different host species, including two native species. In greenhouse nursery inoculations, the two differentBradyrhizobiumstrains successfully nodulate the endemicE. sandwicensis;both strains equally and significantly increased seedling biomass in nursery inoculations. Overall, this work provides a molecular-based framework in which to study potential native and introduced rhizobia on one of the most isolated archipelagos on the planet.
Mapping the Morphology of DNA on Carbon Nanotube-Based Sensors in Solution using X-ray Scattering Interferometry
Authors: Rosenberg Daniel J. , Cunningham Francis J. , Hubbard Joshua D. , Goh Natalie S. , Wang Jeffrey Wei-Ting , Hayman Emily B. , Hura Greg L. , Landry Markita P. , Pinals Rebecca L. 
Published: May 2023

AbstractSingle-walled carbon nanotubes (SWCNTs) with adsorbed single-stranded DNA (ssDNA) are applied as sensors to investigate biological systems, with applications ranging from clinical diagnostics to agricultural biotechnology. Unique ssDNA sequences render SWCNTs selectively responsive to target analytes. However, it remains unclear how the ssDNA conformation on the SWCNT surface contributes to their ultimate functionality, as observations have been constrained to computational models or experiments under dehydrated states that differ substantially from the aqueous biological environments in which the nanosensors are applied. Herein, we demonstrate a direct mode of measuring in-solution ssDNA geometries on SWCNTs via X-ray scattering interferometry (XSI), which leverages the interference pattern produced by AuNP tags conjugated to ssDNA on the SWCNT surface. We employ XSI to quantify distinct surface-adsorbed morphologies for two ssDNA oligomer lengths, conformational changes as a function of ionic strength, and the mechanism of dopamine sensing for a previously established ssDNA-SWCNT nanosensor, with correspondingab initiomodeling for visualization. We show that the shorter oligomer, (GT)6, adopts a highly ordered structure of stacked rings along the SWCNT axis, compared to the longer, less periodic (GT)15wrapping. The presence of dopamine elicits a simultaneous axial elongation and radial constriction of the ssDNA closer to the SWCNT surface. Application of XSI to probe solution-phase morphologies of nanoparticle-based tools will yield insights into sensing mechanisms and inform future design strategies for polymer-functionalized SWCNT technologies.
Colonic mucosal associated invariant T cells in Crohn’s disease have a diverse and non-public T cell receptor beta chain repertoire
Authors: Konecny Andrew J , Shows Donna M , Lord James D 
Published: May 2023

AbstractObjectivesMucosal-Associated Invariant T (MAIT) cells are T cells with a semi-invariant T cell receptor (TCR), recognizing riboflavin precursors presented by a non-polymorphic MR1 molecule. As these precursors are produced by the gut microbiome, we characterized the frequency, phenotype and clonality of MAIT cells in human colons with and without Crohn’s disease (CD).MethodsThe transcriptome of MAIT cells sorted from blood and intestinal lamina propria cells from colectomy recipients were compared with other CD8+T cells. Colon biopsies from an additional ten CD patients and ten healthy controls (HC) were analyzed by flow cytometry. TCR genes were sequenced from individual MAIT cells from these biopsies and compared with those of MAIT cells from autologous blood.ResultsMAIT cells in the blood and colon showed a transcriptome distinct from other CD8 T cells, with more expression of the IL-23 receptor. MAIT cells were enriched in the colons of CD patients, with less NKG2D in inflamed versus uninflamed segments. Regardless of disease, most MAIT cells expressed integrin αEβ7 in the colon but not in the blood, where they were enriched for α4β7 expression. TCR sequencing revealed heterogeneity in the colon and blood, with few public sequences associated with cohorts.ConclusionMAIT cells are enriched in the colons of CD patients and disproportionately express molecules (IL-23R, integrin α4β7) targeted by CD therapeutics, to suggest a pathogenic role for them in CD. Public TCR sequences were neither common nor sufficiently restricted to a cohort to suggest protective or pathogenic antigen-specificities.
The Coviral Portal: Multi-Cohort Viral Loads and Antigen-Test Virtual Trials for COVID-19
Authors: Morgan Alexandra , Contreras Elisa , Yasuda Michie , Dutta Sanjucta , Hamel Donald , Shankar Tarini , Balallo Diane , Riedel Stefan , Kirby James E. , Kanki Phyllis J. , Arnaout Ramy 
Published: May 2023

AbstractBackgroundRegulatory approval of new over-the-counter tests for infectious agents such as SARS-CoV-2 has historically required that clinical trials include diverse groups of specific patient populations, making the approval process slow and expensive. Showing that populations do not differ in their viral loads—the key factor determining test performance—could expedite the evaluation of new tests.Methods46,726 RT-qPCR-positive SARS-CoV-2 viral loads were annotated with patient demographics and health status. Real-world performance of two commercially available antigen tests was evaluated over a wide range of viral loads. An open-access web portal was created allowing comparisons of viral-load distributions across patient groups and application of antigen-test performance characteristics to patient distributions to predict antigen-test performance on these groups.FindingsIn several cases distributions were surprisingly similar where a difference was expected (e.g. smokers vs. non-smokers); in other cases there was a difference that was the opposite direction from expectations (e.g. higher in patients who identified as White vs. Black). Sensitivity and specificity of antigen tests for detecting contagiousness were similar across most groups. The portal is athttps://arnaoutlab.org/coviral/.ConclusionsIn silico analyses of large-scale, real-world clinical data repositories can serve as a timely evidence-based proxy for dedicated trials of antigen tests for specific populations. Free availability of richly annotated data facilitates large-scale hypothesis generation and testing.FundingFunded by the Reagan-Udall Foundation for the FDA (RA and JEK) and via a Novel Therapeutics Delivery Grant from the Massachusetts Life Sciences Center (JEK).
Imputed Gene Expression versus Single Nucleotide Polymorphism in Predicting Gray Matter Phenotypes
Authors: Chen Jiayu , Fu Zening , Iraji Armin , Calhoun Vince D. , Liu Jingyu 
Published: May 2023

ABSTRACTGenetics plays an important role in psychiatric disorders. A clinically relevant question is whether we can predict psychiatric traits from genetics, which holds promise for early detection and tailored intervention. Imputed gene expression, also known as genetically-regulated expression (GRE), reflects the tissue-specific regulatory effects of multiple single nucleotide polymorphisms (SNPs) on genes. In this work, we explored the utility of GRE for trait association studies and how the GRE-based polygenic risk score (gPRS) compared with SNP-based PRS (sPRS) in predicting psychiatric traits. A total of 13 schizophrenia-related gray matter networks identified in another study served as the target brain phenotypes for assessing genetic associations and prediction accuracies in 34,149 individuals from the UK Biobank cohort. GRE was computed leveraging MetaXcan and GTEx tools for 56,348 genes across 13 available brain tissues. We then estimated the effects of individual SNPs and genes separately on each tested brain phenotype in the training set. The effect sizes were then used to compute gPRS and sPRS in the testing set, whose correlations with the brain phenotypes were used to assess the prediction accuracy. The results showed that, with the testing sample size set to 1,138, for training sample sizes from 1,138 up to 33,011, overall both gPRS and sPRS successfully predicted the brain phenotypes with significant correlations observed in the testing set, and higher accuracies noted for larger training sets. In addition, gPRS outperformed sPRS by showing significantly higher prediction accuracies across 13 brain phenotypes, with greater improvement noted for training sample sizes below ∼15,000. These findings support that GRE may serve as the primary genetic variable in brain phenotype association and prediction studies. Future imaging genetic studies may consider GRE as an option depending on the available sample size.