bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Phase 1 First‐in‐Human Single‐Ascending‐Dose Trial With ESB1609, a Selective Agonist to the Sphingosine‐1‐Phosphate Receptor 5
Authors: France Nicholas P. , Rubino Christopher , Safir M. Courtney , Maurer Mari , Duong Tram , Singamsetty Deepika , Abd‐Elaziz Khalid , Chou Thomas , Sankaranarayanan Sethu , Ettema Marieke , Cosford Rebecca , Dogterom Peter , Liu Enchi , Barlow Carrolee 
Published: May 2023

AbstractESB1609 is a small‐molecule sphingosine‐1‐phosphate‐5 receptor–selective agonist designed to restore lipid homeostasis by promoting cytosolic egress of sphingosine‐1‐phosphate to reduce abnormal levels of ceramide and cholesterol in disease. A phase 1 study was conducted in healthy volunteers to determine the safety, tolerability, and pharmacokinetics of ESB1609. Following single oral doses, ESB1609 demonstrated linear pharmacokinetics in plasma and cerebrospinal fluid (CSF) for formulations containing sodium laurel sulfate. Plasma and CSF median time to maximum drug concentration (tmax) were reached by 4–5 hours and 6–10 hours, respectively. The delay in achieving tmax in CSF relative to plasma, likely due to the high protein binding of ESB1609, was also observed in 2 rat studies. Continuous CSF collection via indwelling catheters confirmed that a highly protein‐bound compound is measurable and established the kinetics of ESB1609 in human CSF. Mean plasma terminal elimination half‐lives ranged from 20.2 to 26.8 hours. The effect of either a high‐fat or standard meal increased maximum plasma concentration and area under the concentration‐time curve from time 0 to infinity compared to the fasted state by 2.42–4.34‐fold higher, but tmax and half‐life remained the same irrespective of fed state. ESB1609 crosses the blood‐brain barrier with CSF:plasma ratios ranging between 0.04% and 0.07% across dose levels. ESB1609 demonstrated a favorable safety and tolerability profile at exposures expected to be efficacious.
Ionic‐Liquid Hydrogen‐Bonding Promoted Alcohols Amination over Cobalt Catalyst via Dihydrogen Autotransfer Mechanism
Authors: Ke Zhengang , Wang Yuepeng , Zhao Yanfei , Tang Minhao , Zeng Wei , Wang Ying , Chang Xiaoqian , Han Buxing , Liu Zhimin 
Published: May 2023

AbstractHigher amines are important high‐valuable chemicals with wide applications, and amination of alcohols is a green route to them, which however generally suffers from harsh reaction conditions and use of equivalent base. Herein, we report an ionic‐liquid (IL) hydrogen‐bonding promoted dihydrogen autotransfer strategy for amination of alcohols to higher amines over cobalt catalyst under base‐free conditions. Co(BF4)2 ⋅ 6 H2O complexed with triphos and IL (e. g., tetrabutylphosphonium tetrafluoroborate, [P4444][BF4]) shows high performances for the reaction and is tolerant of a wide scope of amines and alcohols, affording higher amines in good to excellent yields. Mechanism investigation indicates that the [BF4]− anion activates the alcohol via hydrogen bonding, promoting transfer of both hydroxyl H and α‐H atoms of alcohol to the cobalt catalyst to form an aldehyde intermediate and cobalt dihydride complex, which are involved in the subsequent reductive amination. This strategy provides a green and effective route for alcohol amination, which may have promising applications in alcohol‐involved alkylation reactions.
Preanalytical stability of plasma biomarkers for Alzheimer's disease pathology
Authors: Sunde Anita L. , Alsnes Ingvild V. , Aarsland Dag , Ashton Nicholas J. , Tovar‐Rios Diego A. , De Santis Giovanni , Blennow Kaj , Zetterberg Henrik , Kjosavik Svein R. 
Published: May 2023

AbstractIntroductionPlasma tests have demonstrated high diagnostic accuracy for identifying Alzheimer's disease pathology. To facilitate the transition to clinical utility, we assessed whether plasma storage duration and temperature affect the biomarker concentrations.MethodsPlasma samples from 13 participants were stored at +4°C and +18°C. Concentrations of six biomarkers were measured after 2, 4, 6, 8, 10, and 24 h by single molecule array assays.ResultsPhosphorylated tau 181 (p‐tau181), phosphorylated tau 231 (p‐tau231), neurofilament light (NfL), and glial fibrillary acidic protein (GFAP) concentrations were unchanged both when stored at +4°C and +18°C. Amyloid‐β 40 (Aβ40) and amyloid‐β 42 (Aβ42) concentrations were stable for 24 h at +4°C but declined when stored at +18°C for longer than 6 h. This decline did not affect the Aβ42/Aβ40 ratio.DiscussionPlasma samples can be stored for 24 h at +4°C or +18°C and result in valid assay results for p‐tau181, p‐tau231, Aβ42/Aβ40 ratio, GFAP, and NfL.HIGHLIGHTS
Plasma samples were stored for 24 h at +4°C and +18°C, mimicking clinical practice.
Concentrations for Alzheimer's disease biomarkers were measured at six time‐points.
p‐tau181, p‐tau231, NfL, and GFAP concentrations were unchanged during the experiment.
Storage at +18°C affected Aβ40 and Aβ42 concentrations while storage at +4°C did not. The Aβ42/Aβ40 ratio was unaffected.
These plasma tests seem suitable for use in general practice.
Rapid radiation of ant parasitic butterflies during the Miocene aridification of Africa
Authors: Espeland Marianne , Chazot Nicolas , Condamine Fabien L. , Lemmon Alan R. , Lemmon Emily Moriarty , Pringle Ernest , Heath Alan , Collins Steve , Tiren Wilson , Mutiso Martha , Lees David C. , Fisher Stewart , Murphy Raymond , Woodhall Stephen , Tropek Robert , Ahlborn Svenja S. , Cockburn Kevin , Dobson Jeremy , Bouyer Thierry , Kaliszewska Zofia A. , Baker Christopher C. M. , Talavera Gerard , Vila Roger , Gardiner Alan J. , Williams Mark , Martins Dino J. , Sáfián Szabolcs , Edge David A. , Pierce Naomi E. 
Published: May 2023

AbstractAfrica has undergone a progressive aridification during the last 20 My that presumably impacted organisms and fostered the evolution of life history adaptations. We test the hypothesis that shift to living in ant nests and feeding on ant brood by larvae of phyto‐predaceous Lepidochrysops butterflies was an adaptive response to the aridification of Africa that facilitated the subsequent radiation of butterflies in this genus. Using anchored hybrid enrichment we constructed a time‐calibrated phylogeny for Lepidochrysops and its closest, non‐parasitic relatives in the Euchrysops section (Poloyommatini). We estimated ancestral areas across the phylogeny with process‐based biogeographical models and diversification rates relying on time‐variable and clade‐heterogeneous birth‐death models. The Euchrysops section originated with the emerging Miombo woodlands about 22 million years ago (Mya) and spread to drier biomes as they became available in the late Miocene. The diversification of the non‐parasitic lineages decreased as aridification intensified around 10 Mya, culminating in diversity decline. In contrast, the diversification of the phyto‐predaceous Lepidochrysops lineage proceeded rapidly from about 6.5 Mya when this unusual life history likely first evolved. The Miombo woodlands were the cradle for diversification of the Euchrysops section, and our findings are consistent with the hypothesis that aridification during the Miocene selected for a phyto‐predaceous life history in species of Lepidochrysops, with ant nests likely providing caterpillars a safe refuge from fire and a source of food when vegetation was scarce.
Clinical characteristics of heart failure with reduced ejection fraction patients with rare pathogenic variants in dilated cardiomyopathy‐associated genes: A subgroup analysis of the PARADIGM‐HF trial
Authors: Barat Ana , Chen Chien‐Wei , Patel‐Murray Natasha , McMurray John J.V. , Packer Milton , Solomon Scott D. , Desai Akshay S. , Rouleau Jean L. , Zile Michael R. , Attari Zenab , Zhang Cong , Xu Huilei , Hartman Nicole , Hon Claudia , Healey Margaret , Chutkow William , O'Donnell Christopher J. , Jacob Jaison , Lefkowitz Marty , Mendelson Michael M. , Wandel Simon , Yates Denise , Gimpelewicz Claudio 
Published: May 2023

AbstractAimsTo evaluate the prevalence of pathogenic variants in genes associated with dilated cardiomyopathy (DCM) in a clinical trial population with heart failure and reduced ejection fraction (HFrEF) and describe the baseline characteristics by variant carrier status.Methods and resultsThis was a post hoc analysis of the Phase 3 PARADIGM‐HF trial. Forty‐four genes, divided into three tiers, based on definitive, moderate or limited evidence of association with DCM, were assessed for rare predicted loss‐of‐function (pLoF) variants, which were prioritized using ClinVar annotations, measures of gene transcriptional output and evolutionary constraint, and pLoF confidence predictions. Prevalence was reported for pLoF variant carriers based on DCM‐associated gene tiers. Clinical features were compared between carriers and non‐carriers. Of the 1412 HFrEF participants with whole‐exome sequence data, 68 (4.8%) had at least one pLoF variant in the 8 tier‐1 genes (definitive/strong association with DCM), with Titin being most commonly affected. The prevalence increased to 7.5% when considering all 44 genes. Among patients with idiopathic aetiology, 10.0% (23/229) had tier‐1 variants only and 12.6% (29/229) had tier‐1, ‐2 or ‐3 variants. Compared to non‐carriers, tier‐1 carriers were younger (4 years; adjusted p‐value [padj] = 4 × 10−3), leaner (27.8 kg/m2 vs. 29.4 kg/m2; padj = 3.2 × 10−3), had lower ejection fraction (27.3% vs. 29.8%; padj = 5.8 × 10−3), and less likely to have ischaemic aetiology (37.3% vs. 67.4%; padj = 4 × 10−4).ConclusionDeleterious pLoF variants in genes with definitive/strong association with DCM were identified in ∼5% of HFrEF patients from a PARADIGM‐HF trial subset, who were younger, had lower ejection fraction and were less likely to have had an ischaemic aetiology.
Incremental prognostic value of biomarkers in PARADIGM‐HF
Authors: McDowell Kirsty , Campbell Ross , Simpson Joanne , Cunningham Jonathan W. , Desai Akshay S. , Jhund Pardeep S. , Lefkowitz Martin P. , Rouleau Jean L. , Swedberg Karl , Zile Michael R. , Solomon Scott D. , Packer Milton , McMurray John J.V. 
Published: May 2023

AimsIt is uncertain how much candidate biomarkers improve risk prediction when added to comprehensive models including routinely collected clinical and laboratory variables in heart failure.Methods and resultsAldosterone, cystatin C, high‐sensitivity troponin T (hs‐TnT), galectin‐3, growth differentiation factor‐15 (GDF‐15), kidney injury molecule‐1, matrix metalloproteinase‐2 and ‐9, soluble suppression of tumourigenicity‐2, tissue inhibitor of metalloproteinase‐1 (TIMP‐1) and urinary albumin to creatinine ratio were measured in 1559 of PARADIGM‐HF participants. We tested whether these biomarkers, individually or collectively, improved the performance of the PREDICT‐HF prognostic model, which includes clinical, routine laboratory, and natriuretic peptide data, for the primary endpoint and cardiovascular and all‐cause mortality. The mean age of participants was 67.3 ± 9.9 years, 1254 (80.4%) were men and 1103 (71%) were in New York Heart Association class II. During a mean follow‐up of 30.7 months, 300 patients experienced the primary outcome and 197 died. Added individually, only four biomarkers were independently associated with all outcomes: hs‐TnT, GDF‐15, cystatin C and TIMP‐1. When all biomarkers were added simultaneously to the PREDICT‐HF models, only hs‐TnT remained an independent predictor of all three endpoints. GDF‐15 also remained predictive of the primary endpoint; TIMP‐1 was the only other predictor of both cardiovascular and all‐cause mortality. Individually or in combination, these biomarkers did not lead to significant improvements in discrimination or reclassification.ConclusionsNone of the biomarkers studied individually or collectively led to a meaningful improvement in the prediction of outcomes over what is provided by clinical, routine laboratory, and natriuretic peptide variables.
Scutellarein treats neuroblastoma by regulating the expression of multiple targets
Authors: Zhai Chen‐Yang , Fan Ji‐Sheng , Zhang Rong‐Ping 
Published: May 2023

AbstractThe aim of this study is to investigate the effect of scutellarein on the proliferation of neuroblastoma cells and the underlying mechanism. Six cell lines were used with drug intervention. Cell Counting Kit‐8 was used to select the best, namely, SH‐SY5Y, and then its IC50 value was determined. To further investigate the mechanism of scutellarin affecting SH‐SY5Y proliferation, quantitative real‐time polymerase chain reaction (qRT‐PCR) was used to detect the expression levels of 11 factors. Scutellarin administration with 300 μM significantly reduced the number of SH‐SY5Y, especially on the 3rd day of exposure to scutellarin. The IC50 value of scutellarin in SH‐SY5Y cells was determined to be 117.8 μM. But the practical results showed that 300 μM was the optimal concentration of scutellarin. qRT‐PCR further detected upregulated maternally expressed gene 3 (MEG3), oncogene c‐Fos (c‐FOS), and c‐jun and downregulated M2 isoform of pyruvate kinase (PKM2), non‐SMC Condensin I Complex Subunit H (NCAPH), epidermal growth factor receptor (EGFR), transforming growth factor (TGF)‐β1, and TGF‐α, suggesting that scutellarin with 300 μM volume inhibited the survival of SH‐SY5Y by regulating the expression of these 8 factors. Scutellarin could be a novel drug for the treatment of neuroblastoma, and its underlying mechanism may be related to the upregulated levels of MEG3, c‐FOS, and c‐jun and downregulated the expression of PKM2, NCAPH, EGFR, TGF‐β1, and TGF‐α.
UACENet: Uncertain area attention and cross‐image context extraction network for polyp segmentation
Authors: Wang Zhi , Gao Feng , Yu Long , Tian Shengwei 
Published: May 2023

AbstractAccurately segmenting polyp from colonoscopy images is essential for early screening and diagnosis of colorectal cancer. In recent years, with the proposed encoder‐decoder architecture, many advanced methods have been applied to this task and have achieved significant improvements. However, accurate segmentation of polyps has always been a challenging task due to the irregular shape and size of polyps, the low contrast between the polyp and the background in some images, and the influence of the environment such as illumination and mucus. In order to tackle these challenges, we propose a novel uncertain area attention and cross‐image context extraction network for accurate polyp segmentation, which consists of the uncertain area attention module (UAAM), the cross‐image context extraction module (CCEM), and the adaptive fusion module (AFM). UAAM is guided by the output prediction of the adjacent decoding layer, and focuses on the difficult region of the boundary without neglecting the attention to the background and foreground so that more edge details and uncertain information can be captured. CCEM innovatively captures multi‐scale global context within an image and implicit contextual information between multiple images, fusing them to enhance the extraction of global location information. AFM fuses the local detail information extracted by UAAM and the global location information extracted by CCEM with the decoding layer feature for multiple fusion and adaptive attention to enhance feature representation. Our method is extensively experimented on four public datasets and generally achieves state‐of‐the‐art performance compared to other advanced methods.
Dairy pricing policy, production, and water quality: Application to the Chesapeake Bay watershed
Authors: Zhang Zeya , Abler David 
Published: May 2023

AbstractThis study assesses the economic and water quality impacts of implementing a dairy pricing policy under Federal Milk Marketing Order system designed to alleviate milk prices plummet occurred at the beginning of pandemic. Using a 12‐region, positive mathematical programing model of livestock production in the Chesapeake Bay watershed, we find that pricing policy induces significant expansions in dairy sectors, generates higher level of total net revenue in regions having large base‐period dairy sectors. For water quality, we find that policy leads to an increase in nitrogen emissions but a decrease in phosphorus emissions for the livestock industry as a whole in most studied regions.
Exchange rates and macroeconomic fundamentals: Evidence of instabilities from time‐varying factor loadings
Authors: Hillebrand Eric , Mikkelsen Jakob Guldbæk , Spreng Lars , Urga Giovanni 
Published: May 2023

SummaryWe examine the relationship between exchange rates and macroeconomic fundamentals using a two‐step maximum likelihood estimator through which we compute time‐varying factor loadings. Factors are obtained as principal components, extracted from vintage macro‐datasets that combine FRED‐MD and OECD databases. Using 14 currencies over 1990–2021, we show that the loadings on the factors vary considerably over time and increase the percentage of explained variation in exchange rates by an order of magnitude. Time‐varying loadings improve the overall predictive ability of the model, especially during crises, and lead to better forecasts of sign changes in exchange rates.
Skin substitutes based on gellan gum with mechanical and penetration compatibility to native human skin
Authors: Malhotra Deepika , Fattahi Ehsan , Germann Natalie , Flisikowska Tatiana , Schnieke Angelika , Becker Thomas 
Published: May 2023

AbstractThe study reports on a simple system to fabricate skin substitutes consisting of a naturally occurring bacterial polysaccharide gellan gum. Gelation was driven by the addition of a culture medium whose cations induced gellan gum crosslinking at physiological temperature, resulting in hydrogels. Human dermal fibroblasts were incorporated in these hydrogels and their mechanical, morphological, and penetration characteristics were studied. The mechanical properties were determined by means of oscillatory shear rheology, and a short linear viscoelastic regime was noted up to less than 1% of strain amplitude. The storage modulus increased with an increasing polymer concentration. The moduli were in the range noted for native human skin. After 2 weeks of fibroblast cultivation, the storage moduli showed signs of deterioration, so that a culture time of 2 weeks was proposed for further studies. Microscopic and fluorescent staining observations were documented. These depicted a crosslinked network structure in the hydrogels with a homogeneous distribution of cells and an assured cell viability of 2 weeks. H&E staining was also performed, which showed some traces of ECM formation in a few sections. Finally, caffeine penetration experiments were carried out with Franz diffusion cells. The hydrogels with a higher concentration of polymer containing cells showed an improved barrier function against caffeine compared to previously studied multicomponent hydrogels as well as commercially available 3D skin models. Therefore, these hydrogels displayed both mechanical and penetration compatibility with the ex vivo native human skin.
Anatomy, molecular structures, and hyaluronic acid – Gelatin injectable hydrogels as a therapeutic alternative for hyaline cartilage recovery: A review
Authors: Vaca‐González Juan Jairo , Culma Juan José Saiz , Nova Lady Marcela Higuera , Garzón‐Alvarado Diego Alexander 
Published: May 2023

AbstractCartilage damage caused by trauma or osteoarthritis is a common joint disease that can increase the social and economic burden in society. Due to its avascular characteristics, the poor migration ability of chondrocytes, and a low number of progenitor cells, the self‐healing ability of cartilage defects has been significantly limited. Hydrogels have been developed into one of the most suitable biomaterials for the regeneration of cartilage because of its characteristics such as high‐water absorption, biodegradation, porosity, and biocompatibility similar to natural extracellular matrix. Therefore, the present review article presents a conceptual framework that summarizes the anatomical, molecular structure and biochemical properties of hyaline cartilage located in long bones: articular cartilage and growth plate. Moreover, the importance of preparation and application of hyaluronic acid – gelatin hydrogels for cartilage tissue engineering are included. Hydrogels possess benefits of stimulating the production of Agc1, Col2α1‐IIa, and SOX9, molecules important for the synthesis and composition of the extracellular matrix of cartilage. Accordingly, they are believed to be promising biomaterials of therapeutic alternatives to treat cartilage damage.
Identification of psychological flexibility and inflexibility profiles during the COVID‐19 pandemic
Authors: Pakenham Kenneth I. , Landi Giulia , Cattivelli Roberto , Grandi Silvana , Tossani Eliana 
Published: May 2023

AbstractBackgroundThe first coronavirus disease 2019 (COVID‐19) wave and lockdown adversely affected the lives of people in diverse ways.AimsThis study used a person‐centered approach to identify patterns of engagement in the 12 psychological flexibility (PF) and inflexibility (PI) processes to manage the first COVID‐19 wave and lockdown hardships.Materials & MethodsA total of 1035 Italian adults completed an online survey.ResultsLatent profile analyses conducted on the 12 PI/PF processes measured by the Multidimensional Psychological Flexibility Inventory identified five profiles; three reflected gradations of high to low PF with corresponding inverse levels of PI, while two represented more complex relationships between PI and PF. After controlling for relevant socio‐demographic and COVID‐19/lockdown factors, the five profiles differed in mental health (depression, anxiety, and COVID‐19 distress). Essentially a gradient of progressive decreases in all PI processes (except experiential avoidance) corresponded with increments in mental health across all profiles. Two profiles, which evidenced the highest levels of mental health (highly flexible and moderately flexible profiles), also had the greatest proportion of the sample 56.42% (n = 584), and the highest levels of PF and experiential avoidance.DiscussionFindings from this and similar studies suggest intersecting complex relationships among the PI/PF processes that are likely to shift in response to changing contexts. We suggest this network of relationships is better represented by a three‐dimensional PF/PI hexaflex than a simplistic two‐dimensional depiction of the model.ConclusionDistinguishing different PF/PI profiles identified groups most at risk for the adverse mental health impacts of the pandemic and exposed variations in the mental health protective and risk roles of PF and PI processes, respectively, that can inform ACT‐based mental health promotion interventions.
Synthesis of new compounds bearing methyl sulfonyl pharmacophore as selectiveCOX‐2 inhibitor
Authors: Almarsoomi Taha , Osmaniye Derya , Sağlık Begüm Nurpelin , Levent Serkan , Ghani Usman , Özkay Yusuf , Kaplancıklı Zafer Asım 
Published: May 2023

AbstractCyclooxygenase, also known as prostaglandin H2 synthase (PGH2), is one of the most important enzymes in pharmacology because inhibition of COX is the mechanism of action of most nonsteroidal anti‐inflammatory drugs. In this study, ten thiazole derivative compounds had synthesized. The analysis of the obtained compounds was performed by1H NMR and13C NMR methods. By this method, the obtained compounds could be elucidated. The inhibitory effect of the obtained compounds on cyclooxygenase (COX) enzymes was investigated. The encoded compounds5a,5b, and5cwere found to be the most potent compared to the reference compounds ibuprofen (IC50 = 5.589 ± 0.278 μM), celecoxib (IC50 = 0.132 ± 0.004 μM), and nimesulide (IC50 = 1.692 ± 0.077 μM)against COX‐2 isoenzyme. The inhibitory activity of5a,5b, and5cis approximate, but the5aderivative proved to be the most active in the series with an IC50value of 0.180 ± 0.002 μM. The most potent COXs inhibitor was5a, which was further investigated for its potential binding mode by a molecular docking study. Compound5awas found to be localized at the active site of the enzyme, like celecoxib, which has a remarkable effect on COXs enzymes.