bluuebunny/crossref_metadata_2025_split huggingface dataset:
Molecular Mechanism of Labelling Functional Cysteines by Heterocyclic Thiones
Authors: Mihalovits Levente M. , Kollár Levente , Bajusz Dávid , Knez Damijan , Bozovičar Krištof , Imre Tímea , Ferenczy György G. , Gobec Stanislav , Keserű György M. 
Published: October 2023

AbstractHeterocyclic thiones have recently been identified as reversible covalent warheads, consistent with their mild electrophilic nature. Little is known so far about their mechanism of action in labelling nucleophilic sidechains, especially cysteines. The vast number of tractable cysteines promotes a wide range of target proteins to examine; however, our focus was put on functional cysteines. We chose the main protease of SARS‐CoV‐2 harboring Cys145 at the active site that is a structurally characterized and clinically validated target of covalent inhibitors. We screened an in‐house, cysteine‐targeting covalent inhibitor library which resulted in several covalent fragment hits with benzoxazole, benzothiazole and benzimidazole cores. Thione derivatives and Michael acceptors were selected for further investigations with the objective of exploring the mechanism of inhibition of the thiones and using the thoroughly characterized Michael acceptors for benchmarking our studies. Classical and hybrid quantum mechanical/molecular mechanical (QM/MM) molecular dynamics simulations were carried out that revealed a new mechanism of covalent cysteine labelling by thione derivatives, which was supported by QM and free energy calculations and by a wide range of experimental results. Our study shows that the molecular recognition step plays a crucial role in the overall binding of both sets of molecules.
Optical Genome Mapping for Oncology Applications
Authors: Sahajpal Nikhil Shri , Mondal Ashis K. , Hastie Alex , Chaubey Alka , Kolhe Ravindra 
Published: October 2023

AbstractOptical genome mapping (OGM) is a next‐generation cytogenomic technology that has the potential to replace standard‐of‐care technologies used in the genetic workup of various malignancies. The ability to detect various classes of structural variations that include copy number variations, deletions, duplications, balanced and unbalanced events (insertions, inversions, and translocation) and complex genomic rearrangements in a single assay and analysis demonstrates the utility of the technology in tumor research and clinical application. Herein, we provide the methodological details for performing OGM and pre‐ and post‐analytical quality control (QC) checks and describe critical steps that should be performed with caution, probable causes for specific QC failures, and potential method modifications that could be implemented as part of troubleshooting. The protocol description and troubleshooting guide should help new and current users of the technology to improve or troubleshoot the problems (if any) in their workflow. © 2023 Wiley Periodicals LLC.This article was corrected on 10 November 2023. See the end of the full text for details.Basic Protocol: Optical genome mapping
Predictors, mediators, and moderators of response to digital interventions for eating disorders: A systematic review
Authors: McClure Zoe , Fuller‐Tyszkiewicz Matthew , Messer Mariel , Linardon Jake 
Published: October 2023

AbstractObjectiveDigital interventions show promise as an effective prevention or self‐management option for eating disorders (EDs). However, it remains unclear how, for whom, and through what mechanisms they work in this population, as a synthesis of outcome predictors, moderators, and mediators is lacking. This systematic review synthesized empirical research investigating predictors, mediators, and moderators of response to digital interventions for EDs.MethodSix databases were searched (PROSPERO CRD42022295565) for studies that assessed predictors, moderators, or mediators of response (i.e., uptake, drop‐out, engagement, and symptom level change) to a digital prevention or treatment program for EDs. Variables were grouped into several overarching categories (demographic, symptom severity, psychological, etc.) and were synthesized qualitatively across samples without a formally diagnosed ED (typically prevention‐focused) and samples with a formally diagnosed ED (typically treatment‐focused).ResultsEighty‐six studies were included. For studies recruiting samples without a formal diagnosis (n = 70 studies), most predictors explored were statistically unrelated to outcome, although participant age, baseline symptom severity, confidence to change, motivation, and program engagement showed preliminary evidence of prognostic potential. No robust moderators or mediators were identified. Few studies recruiting samples with a formal diagnosis emerged (n = 16), of which no reliable predictors, moderators, or mediators were identified.DiscussionIt remains unclear how, for whom, and under what circumstances digital programs targeting EDs work. We offer several recommendations for future research with the aim of advancing understanding of client characteristics and intervention elements that signal success from this intervention modality.Public SignificanceDigital interventions have shown potential as an effective, scalable, and accessible intervention option for EDs. However, responsiveness varies, so advancing understanding of predictors, mediators, and moderators of outcome to digital interventions for EDs is needed. Such knowledge is important for enabling safe and efficient treatment matching, and for informing future development of effective digital interventions.
Multiple‐Dose, Placebo‐Controlled, Phase I Study of Oral Dolasetron
Authors: Hunt Thomas L. , Cramer Michael , Christy‐Bittel Janna , Shah Ajit K. , Meyerson Laura J. , Benedict Claude R. , Hahne William E 
Published: October 2023

Study Objectives. To evaluate the safety, tolerability, and pharmacokinetics of increasing dose levels of oral dolasetron mesylate, a new 5‐HT3 antagonist.Design. Double‐blind, placebo‐controlled, dose‐ranging phase I study.Setting. A clinical research center.Patients. Forty healthy male volunteers.Interventions. Eight subjects at each dose level were randomized in a ratio of 3:1 to receive either dolasetron mesylate 25, 50, 100, 150, or 200 mg in a single oral dose on days 1 and 9, and twice/day on days 2–8, or placebo for 9 days.Measurements and Main Results. Dolasetron was well tolerated at all dose levels. The adverse event rates for dolasetron‐ and placebo‐treated subjects who experienced at least one adverse event were 80% and 50%, respectively. Most frequently reported by subjects receiving dolasetron were headache, constipation, flatulence, and lightheadedness. They generally were mild, and none was severe. No dose‐response relationship was apparent for any adverse event. There were no clinically significant changes in mean laboratory values or vital signs. Asymptomatic treatment‐related electrocardiographic changes were consistent with the drug's electrophysiologic properties. These changes have been well characterized and have thus far been clinically unimportant. Pharmacokinetics of the reduced metabolite were dose independent, and multiple‐dose exposure of this metabolite can be predicted from its single‐dose values.Conclusion. Oral dolasetron mesylate was well tolerated when administered in doses up to 200 mg/day for 9 days in healthy volunteers.
Combination Therapy with Low‐Dose Lovastatin and Niacin Is as Effective as Higher‐Dose Lovastatin
Authors: Gardner Stephanie F. , Schneider Eric F. , Granberry Mark C. , Carter Inge R. 
Published: October 2023

Study Objectives. To determine if low‐dose lovastatin in combination with niacin causes a greater percentage reduction in low‐density lipoprotein (LDL) cholesterol than lovastatin alone, and to determine if the combination increases the risk of serious adverse effects.Design. Prospective, randomized, open‐label, clinical trial.Setting. Family medicine clinic of a university‐affiliated hospital.Patients. Patients with fasting LDL cholesterol concentrations of at least 150 mg/dl after 4 weeks of dietary stabilization and washout of any cholesterol‐lowering drugs.Interventions. Twenty‐eight patients received lovastatin 20 mg/day for 4 weeks after dietary stabilization and washout. If LDL cholesterol remained above 130 mg/dl (100 mg/dl in patients with coronary artery disease), they were randomized to receive either lovastatin 40 mg/day or a combination of lovastatin 20 mg/day and niacin 500 mg 3 times/day.Measurements and Main Results. There was no difference in actual or percentage reductions of LDL cholesterol, total cholesterol, and triglycerides between the groups. A greater increase in high‐density lipoprotein (HDL) cholesterol occurred with combination therapy (p=0.024). There was no difference in liver function tests, glucose, or uric acid between the therapies. Based on drug‐acquisition cost, combination therapy is approximately 40% less expensive than monotherapy.Conclusion. Low‐dose niacin plus low‐dose lovastatin was as effective as higher‐dose lovastatin in lowering total cholesterol, LDL cholesterol, and triglyceride levels. The combination may offer benefit in raising HDL cholesterol levels.
CYP2D6, N‐Acetylation, and Xanthine Oxidase Activity in Cystic Fibrosis
Authors: Bosso John A. , Liu Qing , Evans William E. , Relling Mary V. 
Published: October 2023

Study Objective. To determine the activity of CYP2D6, N‐acetylation, and xanthine oxidase, three drug‐metabolizing enzyme systems, in patients with cystic fibrosis and compare the findings with those in individuals without the disease.Design. Prospective cohort study.Setting. General pediatrics service.Patients. Fifty‐nine patients with cystic fibrosis and 480 healthy Caucasian volunteers.Interventions. Enzyme activity was determined based on urinary molar metabolite ratios of caffeine and dextromethorphan probes.Measurements and Main Results. The percentage of poor metabolizers of CYP2D6 in patients with cystic fibrosis was not different from that in the control group (p=0.45). N‐Acetylation activity was significantly lower in the patients (p=0.007), but no statistically significant difference was found in xanthine oxidase activity (p=0.12).Conclusion. The activity of these drug‐metabolic pathways does not appear to be increased in cystic fibrosis. Whether the activity of other pathways is increased, thus providing a partial explanation for the generally increased drug clearance in this disease, remains to be determined.
Comparison of Intravenous Diltiazem and Verapamil for the Acute Treatment of Atrial Fibrillation and Atrial Flutter
Authors: Phillips Bradley G. , Gandhi Ashesh J. , Sanoski Cynthia A. , Just Vicki L. , Bauman Jerry L. 
Published: October 2023

Study Objectives. To compare the efficacy and safety of intravenous diltiazem and verapamil in controlling ventricular rate in patients with atrial fibrillation or flutter, and to evaluate the effects of these agents on left ventricular systolic function.Design. Prospective, randomized, double‐blind, crossover study.Setting. University‐affiliated hospital and Veterans Administration hospital.Patients. Seventeen men with atrial fibrillation or flutter with a ventricular rate of 120 beats/minute or higher and a systolic blood pressure of 100 mm Hg or greater.Interventions. Patients received up to two intravenous boluses of either diltiazem or verapamil, followed by an 8‐hour continuous infusion if a therapeutic response was achieved (phase I). After a washout period, patients who responded were crossed over to receive the other drug in a similar fashion (phase II).Measurements and Main Results. At the end of each infusion, the patient's ejection fraction was assessed by gated angiography. Of the 17 men initially randomized, 8 successfully completed both phases I and II. In these patients, baseline mean (± SD) ventricular rates before treatment with intravenous diltiazem and verapamil were 138 ± 15 and 132 ± 9 beats/minute, respectively (NS). At 2 minutes after the initial bolus dose, the mean ventricular rate decreased to 100 ± 13 beats/minute in the diltiazem group compared with 114 ± 17 beats/minute in those receiving verapamil (p<0.05). Mean ventricular rates of 96 ± 11 and 97 ± 9 beats/minute were maintained during the 8‐hour continuous infusion of diltiazem and verapamil, respectively (NS). On completion of the bolus dose(s) and during continuous infusions, there were no significant differences in blood pressures between the groups. Mean ejection fractions were 35.6 ± 13.6% and 35.5 ± 15.4% in the diltiazem and verapamil groups, respectively (NS). For the 17 patients, the mean maximum percentage decreases in blood pressure were not significantly different between groups. However, three patients developed symptomatic hypotension all of whom were randomized to receive verapamil initially.Conclusion. Intravenous diltiazem and verapamil are comparable in terms of efficacy and effect on systolic function in patients with rapid atrial fibrillation and flutter. However, hypotension may limit therapy with verapamil in some patients.
Pharmacokinetics of Amiloride after Inhalation and Oral Administration in Adolescents and Adults with Cystic Fibrosis
Authors: Jones Kristen M. , Liao Edward , Hohneker Kathy , Turpin Stephen , Henry Marianna M. , Selinger Krzysztof , Hsyu Poe‐Hirr , Boucher Richard C. , Knowles Michael R. , Dukes George E. 
Published: October 2023

Study Objective. To compare the pharmacokinetics and systemic exposure of nebulized and oral amiloride in adolescents and adults with mild to moderate cystic fibrosis (CF).Design. Open‐label, randomized, two‐way crossover, single‐dose pharmacokinetic study.Setting. University hospital clinical research unit.Patients. Nine adolescents and 10 adults with mild to moderate CF (forced expiratory volume in 1 sec > 50% predicted, Brasfield score ≥ 15).Interventions. Patients received amiloride solution orally (10 mg of amiloride 1‐mg/ml solution) and by inhalation [4.5 ml amiloride of 1‐mg/ml solution in 12% saline (∼ 3.8 mmol/L) by DeVilbiss 646 nebulizer] during two study phases separated by a 7‐ to 28‐day washout period. Serial blood and urine samples were collected for 48 and 72 hours, respectively.Measurements and Main Results. After oral dosing, the mean ± SD maximum peak concentration (Cmax) was 20.6 ± 10.0 ng/ml at 3.2 ± 1.2 hours in adults and 21.7 ± 4.88 at 2.9 ± 0.6 hours in the adolescents. Mean area under the concentration‐time curve (AUC) from time zero to infinity hours was 275 ± 115 and 254 ± 60 ng•hr/ml in the adult and adolescent groups; half‐life was 16.0 ± 0.7 and 13.4 ± 1.4 hours, respectively. After nebulization, 14 of 19 subjects exhibited two concentration peaks (Cmax1 and Cmax2) with mean values of 1.57 ± 1.67 ng/ml at 0.5 ± 0.2 hours and 1.37 ± 1.21 ng/ml at 4.0 ± 1.0 hours for adults, and 1.49 ± 0.99 ng/ml at 0.5 ± 0.1 hours and 1.52 ± 0.81 ng/ml at 3.3 ± 0.5 hours for adolescents. Estimated mean ± SD dose nebulized was 1.91 ± 0.66 and 2.28 ± 0.30 mg in the adult and adolescent groups, respectively. Mean ± SD AUC from time zero to the last measurable plasma amiloride concentration after inhalation was 14.4 ± 17.6 and 15.4 ± 10.1 ng•hr/ml in the adults and adolescents. No significant adverse events occurred during the study. Pharmacokinetic parameters were not statistically different between the adolescent and adult groups by route of administration. However significant differences in peak amiloride concentration, AUC, and urinary amiloride excretion were evident when comparing oral versus inhalation administration within each group.Conclusions. Mean amiloride plasma concentration peaks and AUC after inhalation were significantly lower than after oral dosing. In addition, the second amiloride plasma concentration peak may be due to oral ingestion of the nebulized amiloride, whereas the earlier Cmax1 after inhalation may be due to pulmonary absorption of amiloride. These results suggest that single‐dose amiloride inhalation in patients with mild to moderate CF results in minimal systemic exposure compared with oral dosing, and that drug disposition is similar in adolescents and adults with CF.
Population Pharmacokinetics of Glyburide in Patients with Well‐Controlled Diabetes
Authors: Tracewell William G. , Stalker Dennis J. , Maloley Pierre A. , Gallagher Thomas F. , Gwilt Peter R. 
Published: October 2023

Study Objectives. To investigate glyburide pharmacokinetics in patients with well‐controlled noninsulin‐dependent diabetes mellitus (NIDDM), and test the hypothesis that intersubject variability in the glyburide dose is due to patient differences in the drug's pharmacokinetics.Methods. Prospective, open‐label study.Setting. University‐affiliated, internal medicine outpatient clinic.Patients. Fifty‐one patients with NIDDM (11 women, 40 men, mean age 56.7 ± 15.3 yrs) receiving oral glyburide and with well‐controlled glycohemoglobin levels 10.0% or below.Intervention. After fasting overnight, patients ingested their regular morning dose of glyburide and then ate breakfast. Blood samples were drawn before dosing and between 0.5–2 hours, 2–5 hours, and 5–10 hours after dosing.Measurements and Main Results. Serum glyburide was assayed by high‐performance liquid chromatography and pharmacokinetics by NONMEM. Glyburide clearance was proportional to weight and greater in older patients (> 60 yrs).Conclusion. Variability in the glyburide dose was not primarily due to intersubject differences in the drug's pharmacokinetics.
Effects of Substrate and Separation Method on Acrosin Amidase Measurements
Authors: Breden Thomas G. , Berg Richard , Plotka Edward D. 
Published: October 2023

ABSTRACT: The purpose of this study was to increase the accuracy and reproducibility of the acrosin amidase assay and to assess the effects of different methods of sperm isolation on total sperm acrosin activity. Specific acrosin activity was measured by the procedure described by Kennedy et al (1989) comparing the usual substrate, N‐α‐benzoyl‐DL‐arginine‐p‐nitroanalide hydrochloride (DL‐BAPNA) with the L‐ (L‐BAPNA) and D‐ (D‐BAPNA) isomers. Activity measurements were also compared on sperm isolated by methods: (1) centrifugation through buffered Ficoll, (2) method 1 plus an additional wash in buffered Ficoll, (3) back addition of supematant from method 1 to spermatozoa isolated by method 2, and (4) swim‐up into synthetic human tubal fluid media (mHTF) and using L‐BAPNA.The specific activity of acrosin was dependent on substrate concentration up to 2.1 mM DL‐BAPNA and 2 mM L‐BAPNA. The maximum reliable solubility of DL‐BAPNA was approximately 2.1 mM in 10% dimethylsulfoxide (DMSO): 90% detergent buffer. There were no solubility constraints for L‐BAPNA through 6.3 mM (> 5 × Km). D‐BAPNA (1 mM) was not hydrolyzed by acrosin. Mean specific acrosin activity was higher using 6.3 mM L‐BAPNA (159 ± 11.4 μIU/106 sperm) than with 2.1 mM DL‐BAPNA (81.4 ± 10.9 μIU/106 sperm; P < 0.001, n = 16). Sperm isolated by methods 2 and 4 had higher specific acrosin activity than sperm isolated by method 1 (P = 0.002). Sperm treated per method 3 had similar acrosin activity as sperm isolated by method 1 (140 ± 14.1 vs. 149 ± 13.8 μIU/106 sperm). The Km for acrosin, calculated through 6.3 mM L‐BAPNA, was 0.6 μIU/106 sperm. L‐BAPNA is superior to DL‐BAPNA as substrate for a clinical acrosin assay, increasing the reproducibility and accuracy of the assay. Simple Ficoll separation is not completely effective at removing acrosin inhibitors and additional separation steps may be necessary to assess true acrosin activity.
Forecasting and stress testing with quantile vector autoregression
Authors: Chavleishvili Sulkhan , Manganelli Simone 
Published: October 2023

SummaryA quantile vector autoregressive (VAR) model, unlike standard VAR, traces the interaction among the endogenous random variables at any quantile. Quantile forecasts are obtained by factorizing the joint distribution in a recursive structure but cannot be obtained from reduced form estimation. Identification strategies and structural quantile impulse response functions are derived as generalization of the VAR model. The model is estimated using real and financial variables for the euro area. The dynamic properties of the system change across quantiles. This is relevant for stress testing exercises, whose goal is to forecast the tail behavior of the economy when hit by large financial and real shocks.
Cover crop performance under a changing climate in continuous corn system over Nebraska
Authors: Birru Girma , Shiferaw Andualem , Tadesse Tsegaye , Wardlow Brian , Jin Virginia L. , Schmer Marty R. , Awada Tala , Kharel Tulsi , Iqbal Javad 
Published: October 2023

AbstractFall‐planted cover crop (CC) within a continuous corn (Zea mays L.) system offers potential agroecosystem benefits, including mitigating the impacts of increased temperature and variability in precipitation patterns. A long‐term simulation using the Decision Support System for Agrotechnology Transfer model was made to assess the effects of cereal rye (Secale cereale L.) on no‐till continuous corn yield and soil properties under historical (1991–2020) and projected climate (2041–2070) in eastern Nebraska. Local weather data during the historical period were used, while climate change projections were based on the Canadian Earth System Model 2 dynamically downscaled using the Canadian Centre for Climate Modelling and Analysis Regional Climate Model 4 under two representative concentration pathways (RCP), namely, RCP4.5 and RCP8.5. Simulations results indicated that CC impacts on corn yield were nonsignificant under historical and climate change conditions. Climate change created favorable conditions for CC growth, resulting in an increase in biomass. CC reduced N leaching under climate change scenarios compared to an average reduction of 60% (7 kg ha−1) during the historical period. CC resulted in a 6% (27 mm) reduction in total water in soil profile (140 cm) and 22% (27 mm) reduction in plant available water compared to no cover crop during historical period. CC reduced cumulative seasonal surface runoff/soil evaporation and increased the rate of soil organic carbon buildup. This research provides valuable information on how changes in climate can impact the performance of cereal rye CC in continuous corn production and should be scaled to wider locations and CC species.
Exploring the versatility of carbohydrates in surimi and surimi products: novel applications and future perspectives
Authors: Sijin Zhang , Zhang Liangzi , Yin Tao , You Juan , Liu Ru , Wang Lan , Huang Qilin , Wang Weisheng , Ma Huawei 
Published: October 2023

AbstractCarbohydrate is one kind of the most important additives in the production of surimi and surimi products, mainly due to its wide range of sources and superior functionality. In recent years, new carbohydrates (oligosaccharides and polysaccharides) have been gradually applied in the production of surimi and surimi products which is mainly driven by consumer requirement on nutritional and the flavors or taste quality and producer requirement on extending the shelf life, like low calorie intake, dietary fiber enrichment, rich taste and improvement of antioxidant properties. Besides anti‐freezing and improvement in gelling ability, novel functionalities have been explored such as fat substitution, improving flavor, antibacterial effect, antioxidant effect and improving three‐dimensional printability. With an in‐depth study of the mechanism of carbohydrate improving the qualities of surimi and surimi products, the application of carbohydrates in surimi would be more effective. Therefore, this review summarizes the new carbohydrates applied in the processing of surimi and surimi products, and their novel functionalities. Additionally, progress of the research on the mechanism of carbohydrate improving the qualities of surimi is also reviewed. © 2023 Society of Chemical Industry.