bluuebunny/crossref_metadata_2025_split huggingface dataset:
Impact of a diabetes disease management program on quality of care and costs: propensity score-matched real-world data from Switzerland
Authors: Carlander Maria , Höglinger Marc , Trottmann Maria , Rhomberg Birgitta , Caviglia Cornelia , Rohrbasser Adrian , Frei Christian , Eichler Klaus 
Published: July 2020

AbstractObjectivesStructured treatment programs have been recommended for management of patients with chronic conditions to overcome ill-coordinated care. We aimed to evaluate a disease management program (DMP) for diabetes mellitus patients in Switzerland.MethodsWe performed a prospective observational study with a propensity score-matched usual care control group from a claims database. We included type-1 and type-2 diabetes patients from a primary care setting. The DMP (intervention) comprised a structured treatment approach with an individual treatment plan, treatment goals and an interprofessional team approach. Our outcome comprehensive measures included quality of life (QOL: EQ-5D-5L), pre-defined indicators for diabetes guideline adherence, number of used services and direct medical costs. We applied a difference-in-difference (DID) approach to compare DMP with usual care (follow-up 1 year). Costs were calculated with non-parametric bootstrapping (2017 Swiss Francs, CHF; conversion rate to Euros: 0.85) from a third-party payer perspective (Swiss health care insurance).ResultsQOL in a sub-sample of 80 patients did not change during follow-up (mean utility 0.89 at baseline and follow-up; p=0.94). Guideline adherence showed slight improvements for DMP. For example, “non-adherence” (baseline DMP: 19%) decreased in the DMP group by −3 %-points (DID; 95%-CI: −0.07 to 0.01) but not in the control group. A general trend emerged, though mostly not statistically significant, with less used services in the DMP group compared to the control group. Costs increased in both groups during follow-up, but the increase was higher in the control group (DID, mean total costs per patient per year: CHF −950.00 [95%-CI: −1959.53 to 59.56]). Such a negative difference-in-difference estimate in favor of DMP also emerged for cost sub-categories (e.g. costs for inpatient and outpatient care).ConclusionsThe structured treatment program under evaluation is a promising approach to improve diabetes care in a Swiss primary care setting but more follow-up data are needed.
Predicting species distributions and community composition using remote sensing products
Authors: Pinto-Ledezma Jesús N. , Cavender-Bares Jeannine 
Published: July 2020

AbstractAccurate predictions of species composition and diversity are critical to the development of conservation actions and management strategies. In this paper using oak assemblages distributed across the conterminous United States as study model, we assessed the performance of stacked species distribution models (S-SDMs) and remote sensing products in building the next-generation of biodiversity models. This study represents the first attempt to evaluate the integrated predictions of biodiversity models—including assemblage diversity and composition—obtained by stacking next-generation SDMs. We found three main results. First, environmental predictors derived entirely from remote sensing products represent adequate covariates for biodiversity modeling. Second, applying constraints to assemblage predictions, such as imposing the probability ranking rule, results in more accurate species diversity predictions. Third, independent of the stacking procedure (bS-SDM versus cS-SDM), biodiversity models do not recover the observed species composition with high spatial resolution, i.e., correct species identities at the scale of individual plots. However, they do return reasonable predictions at macroecological scales (1 km). Our results provide insights for the prediction of assemblage diversity and composition at different spatial scales. An important task for future studies is to evaluate the reliability of combining S-SDMs with direct detection of species using image spectroscopy to build a new generation of biodiversity models to accurately predict and monitor ecological assemblages through time and space.
Studying models of balancing selection using phase-type theory
Authors: Zeng Kai , Charlesworth Brian , Hobolth Asger 
Published: July 2020

ABSTRACTBalancing selection (BLS) is the evolutionary force that maintains high levels of genetic variability in many important genes. To further our understanding of its evolutionary significance, we analyse models with BLS acting on a biallelic locus: an equilibrium model with long-term BLS, a model with long-term BLS and recent changes in population size, and a model of recent BLS. Using phase-type theory, a mathematical tool for analysing continuous time Markov chains with an absorbing state, we examine how BLS affects polymorphism patterns in linked neutral regions, as summarised by nucleotide diversity, the expected number of segregating sites, the site frequency spectrum, and the level of linkage disequilibrium (LD). Long-term BLS affects polymorphism patterns in a relatively small genomic neighbourhood, and such selection targets are easier to detect when the equilibrium frequencies of the selected variants are close to 50%, or when there has been a population size reduction. For a new mutation subject to BLS, its initial increase in frequency in the population causes linked neutral regions to have reduced diversity, an excess of both high and low frequency derived variants, and elevated LD with the selected locus. These patterns are similar to those produced by selective sweeps, but the effects of recent BLS are weaker. Nonetheless, compared to selective sweeps, non-equilibrium polymorphism and LD patterns persist for a much longer period under recent BLS, which may increase the chance of detecting such selection targets. An R package for analysing these models, among others (e.g., isolation with migration), is available.
The genetic architecture of host response reveals the importance of arbuscular mycorrhizae to maize cultivation
Authors: Ramírez-Flores M. Rosario , Perez-Limón Sergio , Li Meng , Barrales-Gamez Benjamin , Olalde-Portugal Víctor , Sawers Ruairidh J. H. 
Published: July 2020

ABSTRACTArbuscular mycorrhizal fungi (AMF) are ubiquitous in cultivated soils, forming symbiotic relationships with the roots of major crop species. Although studies in controlled conditions have demonstrated the potential of the symbiosis to enhance host plant nutrition and alleviate environmental stress, practical difficulties make it hard to estimate the actual benefit in cultivated fields, not least because of the lack of availability of suitable AMF-free controls. Furthermore, the response can vary depending on the plant variety in a manner which is not fully understood. Here, we implemented a novel strategy based on the selective incorporation of AMF-resistance into a genetic mapping population to evaluate maize response in the field. We found AMF to account for about one third of the grain production in a rain-fed medium input field, as well as to impact the relative performance of plant varieties. Characterization of the genetic architecture of host response allowed us to distinguish mycorrhizal benefit from dependence and indicated a trade-off between mycorrhizal and non-mycorrhizal performance, both at the level of individual QTL and genomewide. This approach is applicable to other crop species, permits further mechanistic analysis and is scalable to full yield trials.
Translating insights from the seed metabolome into improved prediction for healthful compounds in oat (Avena sativa L.)
Authors: Campbell Malachy T. , Hu Haixiao , Yeats Trevor H. , Caffe-Treml Melanie , Gutiérrez Lucía , Smith Kevin P. , Sorrells Mark E. , Gore Michael A. , Jannink Jean-Luc 
Published: July 2020

AbstractOat (Avena sativaL.) seed is a rich resource of beneficial lipids, soluble fiber, protein, and antioxidants, and is considered a healthful food for humans. Despite these characteristics, little is known regarding the genetic controllers of variation for these compounds in oat seed. We sought to characterize natural variation in the mature seed metabolome using untargeted metabolomics on 367 diverse lines and leverage this information to improve prediction for seed quality traits. We used a latent factor approach to define unobserved variables that may drive covariance among metabolites. One hundred latent factors were identified, of which 21% were enriched for compounds associated with lipid metabolism. Through a combination of whole-genome regression and association mapping, we show that latent factors that generate covariance for many metabolites tend to have a complex genetic architecture. Nonetheless, we recovered significant associations for 23% of the latent factors. These associations were used to inform a multi-kernel genomic prediction model, which was used to predict seed lipid and protein traits in two independent studies. Predictions for eight of the 12 traits were significantly improved compared to genomic best linear unbiased prediction when this prediction model was informed using associations from lipid-enriched factors. This study provides new insights into variation in the oat seed metabolome and provides genomic resources for breeders to improve selection for health-promoting seed quality traits. More broadly, we outline an approach to distill high-dimensional ‘omics’ data to a set of biologically-meaningful variables and translate inferences on these data into improved breeding decisions.
Genome-wide shifts in histone modifications at early stage of rice infection with Meloidogyne graminicola
Authors: Atighi Mohammad Reza , Verstraeten Bruno , De Meyer Tim , Kyndt Tina 
Published: July 2020

AbstractEpigenetic processes play a crucial role in the regulation of plant stress responses, but their role in plant-pathogen interactions remains poorly understood. Although histone modifying enzymes have been observed to be deregulated in galls induced by root-knot nematodes (RKN,Meloidogyne graminicola) in rice, their influence on plant defence and their genome-wide impact have not been comprehensively investigated.In this study, we applied 3 chemical inhibitors of histone modifying enzymes on rice 24h before inoculation with RKN. Despite their distinct described effects on histone modifications, application of different concentrations led in all cases to reduced susceptibility to RKN. Infection assays on two overexpression lines of histone lysine methyltransferases and one histone deacetylase showed contrasting results in susceptibility, indicating that each histone mark has a specific role in plant defence against RKN in rice. At genome-wide level, three histone marks, H3K9ac, H3K9me2 and H3K27me3 were studied by chromatin-immunoprecipitation (ChIP)-sequencing on RKN-induced galls at 3 days post inoculation. While levels of H3K9ac and H3K27me3 were strongly enriched, H3K9me2 was generally depleted in galls versus control root tips. Differential histone peaks were generally associated with plant defence related genes. In conclusion, our results indicate that histone modifications respond dynamically to RKN infection, and specifically target plant-defence related genes.One-sentence summaryPost-translational histone modifications show a dynamic genome-wide response to root-knot nematode infection in rice and are specifically associated with plant defence genes.
Diversity of tRNA Clusters in the Chloroviruses
Authors: Duncan Garry A. , Dunigan David D. , Van Etten James L. 
Published: July 2020

ABSTRACTViruses rely on their host’s translation machinery for the synthesis of their own proteins. Problems belie viral translation when the host has a codon usage bias (CUB) that is different from an infecting virus with differences in the GC content between the host/virus genome. Here, we evaluate the hypothesis that chloroviruses adapted to host CUB by acquisition and selection of tRNAs that at least partially favor their own CUB. The genomes of 41 chloroviruses comprising three clades of three different algal hosts have been sequenced, assembled and annotated. All 41 viruses not only encode tRNAs, but their tRNA genes are located in clusters. One tRNA gene was common to all three clades of chloroviruses, while differences were observed between clades and even within clades. By comparing the codon usage of one chlorovirus algal host, whose genome has been sequenced and annotated (67% GC content), to that of two of its viruses (40% GC content), we found that the viruses were able to at least partially overcome the host’s CUB by encoding tRNAs that recognize AU-rich codons. In addition, 39/41 chloroviruses encode a putative lysidine synthase, which alters the anticodon of tRNAmetthat normally recognizes AUG to recognize the codon AUA, a codon for isoleucine. This is advantageous to the viruses because the AU-rich codon AUA is 12-13 times more common in the chloroviruses than their host. Evidence is presented that supports the concept that chlorovirus tRNA clusters were acquired prior to events that separated them into the three clades.IMPORTANCEChloroviruses are members of a group of giant viruses that infect freshwater green algae around the world. More than 40 chloroviruses have been sequenced and annotated. In order to propagate efficiently, chloroviruses with low GC content must overcome the high GC content and codon usage bias (CUB) of their hosts. We provide support for one mechanism by which viruses can overcome host CUB. Specifically, the chloroviruses examined herein encode tRNAs whose cognate codons are common in the viruses but not in the host. Virus-encoded tRNAs that recognize AU-rich codons enable more efficient protein synthesis, thus enhancing viral propagation. The tRNA genes are located in clusters and the original tRNA gene cluster was acquired by the most recent common ancestor of the four chlorovirus clades. Furthermore, we show some conservation among all clades, but also substantial variation between and within clades, demonstrating the dynamics of viral evolution.
The S-phase Cyclin Clb5 Promotes rDNA Stability by Maintaining Replication Initiation Efficiency in rDNA
Authors: Goto Mayuko , Sasaki Mariko , Kobayashi Takehiko 
Published: July 2020

ABSTRACTRegulation of replication origins is important for complete duplication of the genome, but the effect of origin activation on the cellular response to replication stress is poorly understood. The budding yeast ribosomal RNA gene (rDNA) forms tandem repeats and undergoes replication fork arrest at the replication fork barrier (RFB), inducing DNA double-strand breaks (DSBs) and genome instability accompanied by copy number alterations. Here we demonstrate that the S-phase cyclin Clb5 promotes rDNA stability. Absence of Clb5 led to reduced efficiency of replication initiation in rDNA but had little effect on the amount of replication forks arrested at the RFB, suggesting that arrival of the converging fork is delayed and forks are more stably arrested at the RFB. Deletion ofCLB5affected neither DSB formation nor its repair at the RFB, but led to an accumulation of recombination intermediates. Therefore, arrested forks at the RFB may be subject to DSB-independent, recombination-dependent rDNA instability. The rDNA instability inclb5Δ was not completely suppressed by the absence of Fob1, which is responsible for fork arrest at the RFB. Thus, Clb5 establishes the proper interval for active replication origins and shortens the travel distance for DNA polymerases, which may reduce Fob1-independent DNA damage.
A Sardinian founder mutation in GP1BB that impacts thrombocytopenia
Authors: Busonero Fabio , Steri Maristella , Orrù Valeria , Sole Gabriella , Olla Stefania , Marongiu Michele , Sidore Carlo , Lai Sandra , Mulas Antonella , Maschio Andrea , Zoledziewska Magdalena , Floris Matteo , Pala Mauro , Forabosco Paola , Asunis Isadora , Pitzalis Maristella , Deidda Francesca , Masala Marco , Caria Cristian Antonio , Barella Susanna , Abecasis Goncalo R. , Schlessinger David , Sanna Serena , Fiorillo Edoardo , Cucca Francesco 
Published: July 2020

AbstractTo investigate the genetic regulation of platelet (PLT) levels we carried out a whole-genome association analysis in 6,528 Sardinians from the general population of the Lanusei valley. We found 6 variants significantly influencing PLT levels, including a novel rare missense mutation (p.Pro27Ser) in the GP1BB protein that is associated with PLT reduction (P=1.17×10−16). This mutation is rare in the SardiNIA population cohort (frequency of 0.45%), even rarer in the rest of the Sardinian island (frequency of 0.16%), and not reported elsewhere. Notably, GP1BB is involved in Bernard-Soulier syndrome (BSS), a rare autosomal recessive bleeding disorder caused by a defect in the platelet GPIb-IX-V protein complex. Consistently, the 57 identified individuals heterozygous for the p.P27S mutation showed mild thrombocytopenia, morphologically enlarged platelets (P=2.13×10−10), and reduced expression of two GPIb-IX-V-complex components: GPIbα (−26.51%, P=3.66×10−8) and GPIX (−24.69%, P=2.66×10−6). Molecular modeling infers a corresponding reduction in the stability of GP1BB. These observations predict that in homozygosity as well as in individuals carrying specific compound heterozygous configurations, this variant likely causes BSS.
Predicting Health Disparities in Regions at Risk of Severe Illness to inform Healthcare Resource Allocations during Pandemics
Authors: Fusillo Tara 
Published: July 2020

AbstractPandemics including COVID-19 have disproportionately affected socioeconomically vulnerable populations. To create a repeatable modelling process to identify regional population centers with pandemic vulnerability, readily available COVID-19 and socioeconomic variable datasets were compiled, and linear regression models were built during the early days of the COVID-19 pandemic. The models were validated later in the pandemic timeline using actual COVID-19 mortality rates in states with high population densities, with New York, New Jersey, Connecticut, Massachusetts, Louisiana, Michigan and Pennsylvania showing the strongest predictive results. Our models have been shared with the Department of Health Commissioners of each of these states as input into a much needed “pandemic playbook” for local healthcare agencies in allocating medical testing and treatment resources.
Chloroquine for treatment of COVID-19 - a pig in a poke?
Authors: Brüggemann R.J. , Moes D.J.A.R. , van Rhee K.P. , van ’t Veer N.E. , Koch B.C.P. , van Rossum M. , den Tweel A. Vermeulen Windsant - van , Reijers M.H.E. , van Kimmenade R.R.J. , Rahamat- Langedoen J.C. , Rettig T.C.D. , van Raalte R. , van Paassen J. , Polderman F.N. , van der Linden P.D. , Frenzel T. , de Mast Q. , Burger D.M. , Schouten J. , van de Veerdonk F.L. , Pickkers P. , ter Heine R. 
Published: July 2020

Structured abstractObjectiveChloroquine has been frequently administered for treatment of coronavirus disease 2019 but there are serious concerns about its efficacy and cardiac safety. Our objective was to investigate the pharmacokinetics and safety of chloroquine in hospitalized COVID-19 patients.DesignA prospective observational study.SettingDutch hospitalsPatientsPatients admitted to the hospital for treatment of COVID-19.InterventionsPharmacokinetic samplingMeasurementsThe plasma concentrations of chloroquine and desethylchloroquine and QTc time.Main ResultsA total of 83 patients were included. The median (IQR) plasma concentration chloroquine during treatment was 1.05 μmol/L (0.63 - 1.55 μmol/L). None of the patients reached exposure exceeding the concentration to inhibit SARS-CoV-2 replication by 90% (IC90) of 6.9 μM. Furthermore, ΔQTc >60 milliseconds occurred after initiation of chloroquine treatment in 34% patients and during treatment QTc ≥500 milliseconds was observed in 46% of patients.ConclusionsRecommended dose chloroquine treatment results in plasma concentrations that are unlikely to inhibit viral replication. Furthermore, the incidence of QTc prolongation was high. The preclinical promise of chloroquine as antiviral treatment in patients with COVID-19 is overshadowed by its cardiac toxicity and lack of effective exposure. It is unlikely that a positive clinical effect will be found with chloroquine for treatment of COVID-19.
NMD is required for timely cell fate transitions by fine-tuning gene expression and controlling translation
Authors: Galimberti Elena , Sehlke Robert , Huth Michelle , Garmhausen Marius , Romeike Merrit , Ramesmayer Julia , Stummer Sarah , Titz-Teixeira Fabian , Herzog Veronika , Chugunova Anastasia , Leesch Katrin Friederike , Holcik Laurenz , Weipoltshammer Klara , Santini Laura , Lackner Andreas , von Haeseler Arndt , Bücker Christa , Pauli Andrea , Schoefer Christian , Ameres Stefan L. , Smith Austin , Beyer Andreas , Leeb Martin 
Published: July 2020

ABSTRACTCell fate transitions depend on balanced rewiring of transcription and translation programmes to mediate ordered developmental progression. Components of the nonsense-mediated mRNA decay (NMD) pathway have been implicated in regulating embryonic stem cell (ESC) differentiation, but the exact mechanism is unclear. Here we show that NMD controls the translation initiation factorEif4a2and its premature termination codon encoding isoform (Eif4a2PTC). NMD deficiency leads to translation of a specific truncated Eif4a2 protein, which elicits increased translation rates and causes significant delays in mouse ESC differentiation. Thereby a previously unknown feedback loop between NMD and translation initiation is established. Our results illustrate a clear hierarchy between KOs in severity of target deregulation and differentiation phenotype (Smg5>Smg6>Smg7), which highlights heterodimer-independent functions for Smg5 and Smg7. Together, our findings expose an intricate link between mRNA stability and translation initiation control that must be maintained for normal dynamics of cell state transitions.
Most of Tobacco Male Meiocytes Are Involved in Intercellular Nuclear Migration at the First Meiotic Prophase
Authors: Mursalimov Sergey , Ohno Nobuhiko , Matsumoto Mami , Bayborodin Sergey , Deineko Elena 
Published: July 2020

AbstractSerial block-face scanning electron microscopy was used here to study tobacco male meiosis. Three-dimensional ultrastructural analyses revealed that intercellular nuclear migration (INM) occurs in 90–100% of tobacco meiocytes. At the very beginning of meiosis, every meiocyte connected with neighboring cells by more than 100 channels was capable of INM. At leptotene and zygotene, the nucleus in most tobacco meiocytes approached the cell wall and formed nuclear protuberances (NPs) that crossed the cell wall through the channels and got into the cytoplasm of a neighboring cell. The NPs did not separate from the migrating nuclei and never produced micronuclei. Approximately 70% of NPs reached nuclei of neighboring cells. The NPs and the nuclei they reached got very close, and the gap between their nuclear membranes became indistinguishable in some cases. At pachytene, NPs detached from the nuclei of neighboring cells and came back into their own cells. After that, the INM stopped. The reason for such behavior of nuclei is unclear. INM probably causes a short-lived fusion of two nuclei and thus has a potential to form aneuploid or unreduced pollen. We consider INM a normal part of tobacco meiosis.