bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cost-effectiveness of sotagliflozin for the treatment of patients with diabetes and recent worsening heart failure
Authors: Kim Jaehong , Wang Shanshan , Sikirica Slaven , Shafrin Jason 
Published: December 2023

AbstractBackgroundThe efficacy and safety of sotagliflozin, a novel therapy for the treatment of patients with heart failure, was demonstrated in SOLOIST-WHF, but its economic value is yet to be determined. This study assesses the cost-effectiveness of sotagliflozin for the treatment of patients hospitalized with heart failure and comorbid diabetes.MethodsAn economic model with a Markov structure was created for patients hospitalized for heart failure with comorbid diabetes. Outcomes of interest included hospital readmissions, emergency department visits, and all-cause mortality measured over a 30-year time horizon. Baseline event frequencies were derived from published real-world data studies; sotagliflozin’s efficacy was estimated from SOLOIST-WHF. Health benefits were synthesized using quality-adjusted life years. Costs included pharmaceutical costs, rehospitalization, emergency room visits and adverse events. Economic value was measured using the incremental cost effectiveness ratio.ResultsSotagliflozin use decreased annualized rehospitalization rates by 34.5% (0.228 vs. 0.348, difference: -0.120), annualized emergency department visits by 40.0% (0.091 vs. 0.153, difference: -0.061), and annualized mortality by 18.0% (0.298 vs. 0.363, difference: -0.065) relative to standard of care, resulting in a net gain in quality adjusted life-years of 0.425 for sotagliflozin vs. standard of care. Incremental costs using sotagliflozin increased by $19,374 over the lifetime of the patient, driven largely by increased pharmaceutical cost. Estimated incremental cost effectiveness ratio was $45,596 per quality adjusted life-year.ConclusionsSotagliflozin is a cost-effective addition to standard of care for patients hospitalized with heart failure and comorbid diabetes.
Three-dimensional histology reveals dissociable human hippocampal long axis gradients of Alzheimer’s pathology
Authors: Ortega-Cruz Diana , Bress Kimberly S. , Gazula Harshvardhan , Rabano Alberto , Iglesias Juan Eugenio , Strange Bryan A. 
Published: December 2023

AbstractINTRODUCTIONThree-dimensional (3D) histology analyses are essential to overcome sampling variability and understand pathological differences beyond the dissection axis. We present Path2MR, the first pipeline allowing 3D reconstruction of sparse human histology without an MRI reference. We implemented Path2MR with post-mortem hippocampal sections to explore pathology gradients in Alzheimer’s Disease.METHODSBlockface photographs of brain hemisphere slices are used for 3D reconstruction, from which an MRI-like image is generated using machine learning. Histology sections are aligned to the reconstructed hemisphere and subsequently to an atlas in standard space.RESULTSPath2MR successfully registered histological sections to their anatomical position along the hippocampal longitudinal axis. Combined with histopathology quantification, we found an expected peak of tau pathology at the anterior end of the hippocampus, while amyloid-β displayed a quadratic anterior-posterior distribution.CONCLUSIONPath2MR, which enables 3D histology using any brain bank dataset, revealed significant differences along the hippocampus between tau and amyloid-β.
Chronic exposure to predator cues fails to elicit plastic responses or transgenerational effects in banded crickets
Authors: Dalos Jeremy , Dochtermann Ned A. 
Published: December 2023

AbstractPlasticity is a major feature of behavior and particularly important for how animals respond to predators. While animals frequently show plastic responses when directly exposed to predators, with these exposures even leading to permanent behavioral changes and transgenerational effects, whether indirect cues of predator presence can elicit similarly severe responses is unclear. We exposed banded crickets (Gryllodes siglattus) to cues of predator presence throughout development and compared their behavior—as well as the behavior of their offspring—to individuals who had not been reared in the presence of predator cues. Contrary to findings in bothG. sigilattusand related species, we did not detect either developmental plasticity in the form of differences between adult behavior or differences in offspring behavior. These findings suggest that chronic exposure to cues of predator presence have a substantially different affect on behaviors than does direct exposure to predators. How habituation might interact with developmental plasticity and transgenerational effects requires further investigation.Significance StatementPrevious research has established that exposure to predators elicits behavioral plasticity, including life-long effects, as well as transgenerational effects. Here we show that chronic exposure to cues of predator presence throughout development, with a resulting potential for habituation, results in neither differences in adult behavior or transgenerational effects. This suggests an important role for habituation in how plasticity manifests within and between generations
G1 length dictates H3K27me3 landscapes
Authors: Trouth Abby , Ravichandran Kamesh , Gafken Philip R , Martire Sara , Boyle Gabriel E. , Veronezi Giovana M. B. , La Van , Namciu Stephanie J. , Banaszynski Laura A. , Sarthy Jay F. , Ramachandran Srinivas 
Published: December 2023

ABSTRACTStem cells have lower facultative heterochromatin as defined by trimethylation of histone H3 lysine 27 (H3K27me3) compared to differentiated cells. However, the mechanisms underlying these differential H3K27me3 levels remain elusive. Because H3K27me3 levels are diluted two-fold in every round of replication and then restored through the rest of the cell cycle, we reasoned that the cell cycle length could be a key regulator of total H3K27me3 levels. Here, we propose that a fast cell cycle restricts H3K27me3 levels in stem cells. To test this model, we determined changes to H3K27me3 levels in mESCs globally and at specific loci upon G1 phase lengthening – accomplished by thymidine block or growth in the absence of serum (with the “2i medium”). H3K27me3 levels in mESC increase with G1 arrest when grown in serum and in 2i medium. Additionally, we observed via CUT&RUN and ChIP-seq that regions that gain H3K27me3 in G1 arrest and 2i media overlap, supporting our model of cell cycle length as a critical regulator of the stem cell epigenome and cellular identity. Furthermore, we demonstrate the inverse effect – that G1 shortening in differentiated cells results in a loss of H3K27me3 levels. Finally, in tumor cells with extreme H3K27me3 loss, lengthening of the G1 phase leads to H3K27me3 recovery despite the presence of the dominant negative, sub-stoichiometric H3.1K27M mutation. Our results indicate that G1 length is an essential determinant of H3K27me3 landscapes across diverse cell types.
The small iron-deficiency-induced protein OLIVIA and its relation to the bHLH transcription factor POPEYE
Authors: Lichtblau Daniela M. , Baby Dibin , Khan Mather , Trofimov Ksenia , Ari Yunus , Schwarz Birte , Bauer Petra 
Published: December 2023

AbstractIron (Fe) is a crucial micronutrient needed in many metabolic processes. To balance needs and potential toxicity, plants control the amount of Fe they take up and allocate to leaves and seeds during their development. One important regulator of this process is POPEYE (PYE). PYE is a Fe deficiency-induced key bHLH transcription factor (TF) for allocation of internal Fe in plants. In the absence of PYE, there is altered Fe translocation and plants develop a leaf chlorosis.NICOTIANAMINE SYNTHASE4(NAS4),FERRIC-REDUCTION OXIDASE3(FRO3), andZINC-INDUCED FACILITATOR1(ZIF1) genes are expressed at higher level inpye-1indicating that PYE represses these genes. PYE activity is controlled in a yet unknown manner. Here, we show that a small Fe deficiency-induced protein OLIVIA (OLV) can interact with PYE. OLV has a conserved C-terminal motif, that we named TGIYY. Through deletion mapping, we pinpointed that OLV TGIYY and several regions of PYE can be involved in the protein interaction. AnOLVoverexpressing (OX) mutant line exhibited an enhancedNAS4gene expression. This was a mild Fe deficiency response phenotype that was related to PYE function. Leaf rosettes ofolvmutants remained smaller than those of wild type, indicating that OLV promotes plant growth. Taken together, our study identified a small protein OLV as a candidate that may connect aspects of Fe homeostasis with regulation of leaf growth.HighlightsOLIVIA (OLV), a small protein, can interact with the bHLH transcription factor POPEYE (PYE)OLV has a conserved motif, named TGIYY, that can be involved in protein interaction with PYEOLV mutant plants have mild phenotypes related with PYE andNAS4regulation.OLV promotes rosette growth.
Post-GWAS Prioritization of Genome-Phenome Association in Sorghum
Authors: Pal Debasmita , Schaper Kevin , Thompson Addie , Guo Jessica , Jaiswal Pankaj , Lisle Curtis , Cooper Laurel , LeBauer David , Thessen Anne , Ross Arun 
Published: December 2023

AbstractGenome-Wide Association Studies (GWAS) are widely used to infer the genetic basis of traits in organisms, yet selecting appropriate thresholds for analysis remains a significant challenge. In this study, we developed the Sequential SNP Prioritization Algorithm (SSPA) to elucidate the genetic underpinnings of two key phenotypes inSorghum bicolor: maximum canopy height and maximum growth rate. Utilizing a subset of the Sorghum Bioenergy Association Panel cultivated at the Maricopa Agricultural Center in Arizona, our objective was to employ GWAS with specific permissive-filtered thresholds to identify the genetic markers associated with these traits, allowing for a broader collection of explanatory candidate genes. Following this, our proposed method incorporates a feature engineering approach based on statistical correlation coefficient to reveal patterns between phenotypic similarity and genetic proximity across 274 accessions. This approach helps prioritize Single Nucleotide Polymorphisms (SNPs) likely to be associated with the studied phenotype. Additionally, we evaluated the impact of SSPA by considering all variants (SNPs) as inputs, without any GWAS filtering, as a complementary analysis. Empirical evidence including ontology- based gene function, spatial and temporal expression, and similarity to known homologs, demonstrated that SSPA effectively prioritizes SNPs and genes influencing the phenotype of interest, providing valuable insights for functional genetics research.
OOPS: Object-Oriented Polarization Software for analysis of fluorescence polarization microscopy images
Authors: Dean William F. , Nawara Tomasz J. , Albert Rose M. , Mattheyses Alexa L. 
Published: December 2023

AbstractMost essential cellular functions are performed by proteins assembled into larger complexes. Fluorescence Polarization Microscopy (FPM) is a powerful technique that goes beyond traditional imaging methods by allowing researchers to measure not only the localization of proteins within cells, but also their orientation or alignment within complexes or cellular structures. FPM can be easily integrated into standard widefield microscopes with the addition of a polarization modulator. However, the extensive image processing and analysis required to interpret the data have limited its widespread adoption. To overcome these challenges and enhance accessibility, we introduce OOPS (Object-Oriented Polarization Software), a MATLAB-based analysis tool tailored for FPM data. This work highlights the distinctive features of our software, which empower researchers to efficiently manage large datasets; detect and analyze individual structures; conduct population assessments based on morphology, intensity, and polarization-specific parameters; and create publication-quality visualizations, all within a user-friendly graphical interface. Importantly, OOPS is adaptable to various sample types, labeling techniques, and imaging setups, facilitating in-depth analysis of diverse polarization-sensitive samples. Here, we demonstrate the power and versatility of our approach by applying OOPS to FPM images of both punctate and filamentous structures. OOPS is freely available under the GNU GPL 3.0 license and can be downloaded athttps://github.com/Mattheyses-Lab/OOPS.
Persistence of genetically engineered canola populations in the U.S. and the adventitious presence of transgenes in the environment
Authors: Travers Steven , Bishop D. Bryan , Sagers Cynthia 
Published: December 2023

AbstractFeralization of genetically engineered (GE) crops increases the risk that transgenes will become integrated into natural and naturalizing plant populations. A key assumption of the management of GE crops is that populations of escaped plants are short-lived and that the risks they pose, therefore, are limited. However, few populations of escaped crop plants have been tracked over the long term so our understanding of their persistence in ruderal or natural landscapes is limited. In 2021, we repeated a large-scale road survey of feral GE canola populations in North Dakota, USA, initially conducted in 2010. Our objectives were to determine the current distribution of feral canola populations, and to establish the relative frequency of GE and non-GE phenotypes in populations of canola throughout North Dakota, where most of the canola in the USA is grown. Our results indicate that, although the incidence of feral canola was less in 2021 than 2010, escaped canola populations remain common throughout the state. The prevalence of alternate forms of GE herbicide resistance changed between surveys, and we found an overabundance of non-GE plants compared to the frequency of non-transgenic forms in cultivation. Indirect evidence that canola escaped from cultivation has established persistent populations outside of management includes finding plants with multiple transgenic traits, and locating populations far from transportation routes. We conclude that feral canola populations expressing transgenic herbicide resistance are established outside of cultivation, that they may be under selection for loss of the transgene, but that they nonetheless pose long-term risks by harboring transgenes in the unmanaged landscape.
Evolutionary analyses of IDRs reveal widespread signals of conservation
Authors: Singleton Marc , Eisen Michael 
Published: December 2023

AbstractIntrinsically disordered regions (IDRs) are segments of proteins without stable three-dimensional structures. As this flexibility allows them to interact with diverse binding partners, IDRs play key roles in cell signaling and gene expression. Despite the prevalence and importance of IDRs in eukaryotic proteomes and various biological processes, associating them with specific molecular functions remains a significant challenge due to their high rates of sequence evolution. However, by comparing the observed values of various IDR-associated properties against those generated under a simulated model of evolution, a recent study found most IDRs across the entire yeast proteome contain conserved features. Furthermore, it showed clusters of IDRs with common “evolutionary signatures,”i.e.patterns of conserved features, were associated with specific biological functions. To determine if similar patterns of conservation are found in the IDRs of other systems, in this work we applied a series of phylogenetic models to over 8,500 orthologous IDRs identified in theDrosophilagenome to dissect the forces driving their evolution. By comparing models of constrained and unconstrained continuous trait evolution using the Brownian motion and Ornstein-Uhlenbeck models, respectively, we identified signals of widespread constraint, indicating conservation of distributed features is mechanism of IDR evolution common to multiple biological systems. In contrast to the previous study in yeast, however, we observed limited evidence of IDR clusters with specific biological functions, which suggests a more complex relationship between evolutionary constraints and function in the IDRs of multicellular organisms.
Genetic requirements for uropathogenicE. coliproliferation in the bladder cell infection cycle
Authors: Mediati Daniel G. , Blair Tamika A. , Costas Ariana , Monahan Leigh G. , Söderström Bill , Charles Ian G. , Duggin Iain G. 
Published: December 2023

ABSTRACTUropathogenicEscherichia coli(UPEC) requires an adaptable physiology to survive the wide range of environments experienced in the host, including gut and urinary tract surfaces. To identify UPEC genes required during intracellular infection, we developed a transposon-directed insertion-site sequencing (TraDIS) approach for cellular infection models and searched for genes in a library of ∼20,000E. coliUTI89 transposon-insertion mutants that are specifically required for growth in M9-glycerol minimal medium, and at the distinct stages of infection of cultured bladder epithelial cells. Some of the functional requirements apparent for growth in M9-glycerol overlapped with those for the intracellular stage of infection, notably nutrient utilization, polysaccharide and macromolecule precursor biosynthesis, and cell envelope stress tolerance. Two genes implicated in both conditions were confirmed through independent gene deletion studies:neuC(sialic acid capsule biosynthesis) andhisF(histidine biosynthesis). Distinct sets of UPEC genes were also implicated in bacterial dispersal, where UPEC erupt from bladder cells in highly filamentous or motile forms upon exposure to human urine, and during recovery from infection in rich (LB) medium. Genes linked to septal peptidoglycan processes,ytfBanddedD, appeared to play roles in dispersal and may help stabilize cell division or the envelope during envelope stress created during infection. Our findings support a view that the host intracellular environment and infection cycle are multi-nutrient limited and create stress that demand an array of biosynthetic, cell envelope integrity and biofilm-related functions of UPEC.IMPORTANCEUrinary tract infections (UTIs) are one of the most frequent infections worldwide. UropathogenicEscherichia coli(UPEC), which accounts for ∼80 % of UTIs, must rapidly adapt to highly variable host environments, such as the gut, bladder sub-surface and urine. In this study, we searched for UPEC genes required for bacterial growth and survival throughout the cellular infection cycle. Genes required forde novosynthesis of biomolecules and cell envelope integrity appeared to be important, and other genes were also implicated in bacterial dispersal and recovery from infection of cultured bladder cells. With further studies of individual gene function, their potential as therapeutic targets may be realized. This study expands knowledge of the UTI infection cycle and establishes an approach to genome-wide functional analyses of stage-resolved microbial infections.
Objective and Subjective Assessments of Exercise Burden in Masters Athletes Are Poorly Correlated
Authors: Lewis Jennifer , Bentley Robert F. , Connelly Kim A. , Dorian Paul , Goodman Jack M. 
Published: December 2023

ABSTRACTAccurate quantification of exercise volume (burden) is crucial for understanding links between exercise and cardiovascular outcomes in older endurance athletes (EA). Exercise burden, an integral of intensity and duration (MET·min), is typically determined from subjective self-reports but has uncertain accuracy. We studied 40 EAs (41 to 69 yrs., 50% female) with >10 yrs. training history, during a typical outdoor cycling training session (42 km). Subjective self-reports were related to cardiac (HR·min) and metabolic (MET·min) components of exercise burden, monitored continuously. Subjective self-reports were highly variable and underestimated objective metrics of exercise intensity. Discordance was observed between metabolic and cardiac burden as less fit individuals accrued greater cardiac (14039±2649 vs. 11784±1132 HR·min, P<0.01) but lower metabolic burden (808±59 vs. 858±61 MET·min,P<0.05) vs. higher fit EA. Caution is advised in interpreting MET·min estimates from self-reports, urging objective measurement of cardiac burden for further insights into the risk-benefit relationship of long-term exercise.
Genetic Polymorphisms and Post-Stroke Upper Limb Motor Improvement – A Systematic Review and Meta-Analysis
Authors: Subramanian Sandeep K. , Morgan Riley T. , Rasmusson Carl , Shepherd Kayla M. , Li Carol L 
Published: December 2023

AbstractBackgroundPost-stroke upper limb (UL) motor improvement is associated with adaptive neuroplasticity and motor learning. Both intervention-related (including provision of intensive, variable, and task-specific practice) and individual-specific factors (including the presence of genetic polymorphisms) influence improvement. In individuals with stroke, most commonly, polymorphisms are found in Brain Derived Neurotrophic Factor (BDNF), Apolipoprotein (APOE) and catechol-O-methyltransferase (COMT). These involve a replacement of cystine by arginine (APOEε4) or one or two valines by methionine (BDNF: val66met, COMT: val158met). However, the implications of these polymorphisms on post-stroke UL motor improvement specifically have not yet been elucidated.ObjectiveExamine the influence of genetic polymorphism on post-stroke UL motor improvement.DesignSystematic Review and Meta-AnalysisMethodsWe conducted a systematic search of the published literature in English language of using standard methodology. The modified Downs and Black checklist helped assess study quality. We compared change in UL motor impairment and activity scores between individuals with and without the polymorphisms. Meta-analyses helped assess change in motor impairment scores based upon a minimum of two studies per time point. Effect sizes (ES) were quantified based upon the Rehabilitation Treatment Specification System as follows: small (0.08–0.18), medium (0.19–0.40) and large (≥0.41).ResultsWe retrieved 10 (four good and six fair quality) studies. Compared to those with BDNF val66met polymorphism, meta-analyses revealed lower motor impairment scores (large ES) in those without the polymorphism at intervention completion (0.5, 95% CI: 0.11-0.88) and at retention (0.58, 95% CI: 0.06-1.11). Presence of CoMT val158met polymorphism had similar results, with higher levels of improvement in impairment (large ES ≥1.5) and activity scores (large ES ranging from 0.5-0.76) in those without the polymorphism. Presence of APOEε4 form did not influence UL motor improvement.ConclusionBDNF val66met and COMT val158met polymorphisms negatively influence UL motor improvement in impairment and activity scores.Registrationhttps://osf.io/wk9cf/