bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Phase 1 Pharmacokinetic Drug Interaction Study of Belumosudil Coadministered With CYP3A4 Inhibitors and Inducers and Proton Pump Inhibitors
Authors: Schueller Olivier , Willson Ashley , Singh Nand , Lohmer Lauren , Alabanza Anginelle , Patel Jeegar 
Published: March 2022

AbstractBelumosudil is a selective Rho‐associated protein kinase 2 inhibitor. Inhibition of Rho‐associated protein kinase 2 has emerged as a promising treatment for chronic graft‐versus‐host disease by restoring immune homeostasis and reducing fibrosis. In vitro assessments have suggested that metabolism of belumosudil is primarily dependent on cytochrome P450 (CYP) 3A4 activity and that the solubility of belumosudil is pH dependent. As such, this 2‐part clinical drug‐drug interaction study was conducted to assess the effect of itraconazole (a strong CYP3A4 inhibitor), rifampicin (a strong CYP3A4 inducer), rabeprazole, and omeprazole (both proton pump inhibitors) on the pharmacokinetics of belumosudil. No clinically relevant change in belumosudil exposure was observed following a 200‐mg single oral dose of belumosudil with itraconazole; however, exposure of main metabolite, KD025m2, was decreased. Consistent with the proposed metabolic pathway of belumosudil, the strong CYP3A4 inducer rifampicin significantly decreased exposure of belumosudil and KD025m2 and increased KD025m1 exposure. When a 200‐mg single oral dose of belumosudil was coadministered with both rabeprazole and omeprazole, parent and metabolite exposures were largely reduced, suggesting that belumosudil dosage should be increased when given with PPIs. Administration of belumosudil with and without perpetrator drugs was safe, and no notable adverse events were reported.
Clinical Pharmacology of Insulin Aspart Biosimilar GP40071: Pharmacokinetic/Pharmacodynamic Comparability in Hyperinsulinemic Euglycemic Clamp Procedure
Authors: Drai Roman V. , Karonova Tatiana L. , Mayorov Alexander Y. , Makarenko Igor E. , Dorotenko Artem R. , Kulesh Viktoria S. , Kovalik Vladislav V. , Andreeva Alena T. 
Published: March 2022

AbstractInsulin aspart is a short‐acting insulin analogue that is used to control postprandial glycemia levels in diabetic patients. The aim of this clinical trial was to compare the pharmacokinetics and pharmacodynamics of GP40071 (GP‐Asp) and NovoRapid Penfill (Novo‐Asp) in a hyperinsulinemic euglycemic clamp (HEC). This trial was conducted as a part of a GP40071 biosimilar clinical development program. This was a phase I randomized, double‐blind, two‐period crossover study. Twenty‐six healthy male volunteers aged 18 to 45 years who met the inclusion criteria underwent the procedure of an HEC following a single subcutaneous injection of 0.3 IU/kg of either GP‐Asp or Novo‐Asp into the abdomen. After doses, plasma glucose levels were monitored every 5 minutes for 8 hours. The adjustment of the glucose infusion rate (GIR) was based on the blood glucose measurements. The GIR values were used to evaluate the PD profiles of the studied drugs. Regular blood sampling was performed during the study to obtain sufficient pharmacokinetic data. The 90% confidence intervals for the geometric mean ratios of the pharmacokinetic (AUCins.0‐t, Cins.max) and pharmacodynamic (GIRmax, AUCGIR0‐t) parameters of GP‐Asp were within the 80%–125% comparability limits. The safety profiles of the drugs were also comparable. Bioequivalence, similar PD, and safety of GP‐Asp and Novo‐Asp were demonstrated.
Absolute Bioavailability, Mass Balance, and Metabolic Profiling Assessment of [14C]‐Belumosudil in Healthy Men: A Phase 1, Open‐Label, 2‐Part Study
Authors: Schueller Olivier , Skucas Ed , Regev Galit , Shaw Iain , Singh Nand , Sanghvi Mitesh , Croft Marie , Lohmer Lauren , Alabanza Anginelle , Patel Jeegar 
Published: March 2022

AbstractBelumosudil is a selective Rho‐associated coiled‐coil containing protein kinase 2 (ROCK2) inhibitor. ROCK2 has been shown to drive proinflammatory response and fibrosis that occurs with chronic graft‐versus‐host disease; therefore, inhibition of ROCK2 has emerged as a therapeutic target for chronic graft‐versus‐host disease. In this phase 1 two‐part study, the pharmacokinetics, mass balance, and metabolic profile of belumosudil were evaluated after single doses of unlabeled belumosudil oral tablets (200 mg), radiolabeled belumosudil intravenous (IV) microtracer infusions (100 μg), and radiolabeled oral capsules (200 mg). Absolute bioavailability based on area under the plasma concentration–time curve from time 0 to infinity for the oral dose/area under the plasma concentration–time curve from time 0 to infinity for the IV dose was calculated as 63.7%. Radiolabeled IV microtracer dosing demonstrated a low extraction ratio and distribution of belumosudil into tissues. The majority of total radioactivity was recovered in feces, with minimal amounts recovered in urine, suggesting minimal renal elimination of belumosudil. In addition to parent and main metabolite KD025m2, metabolites identified in plasma included the phase 2 metabolites O‐dealkylated belumosudil sulfate and belumosudil glucuronide. These metabolites (with the exception of the glucuronide) in addition to monohydroxy‐belumosudil, and belumosudil diol were identified in feces. No metabolites in urine accounted for >10% of the radioactive dose.
User‐level parallel file system: Case studies and performance optimizations
Authors: Zou Yanliang , Chen Chen , Deng Tongliang , Zhang Jian , Zhu Xiaomin , Chen Si , Yin Shu 
Published: March 2022

AbstractUser‐level file systems are usually adopted to bridge the gap between efficacy and efficiency of file system developments for new applications' I/O demands. And the widely known user‐space file system framework, FUSE, is commonly utilized to deployed user‐level file systems. This article first uses a popular stack‐able file system as a case study to exam how FUSE affects I/O performance. Based on the testing and analytical results, this article then presents SHC, an implementation method to implement a user‐level file system without FUSE intervention. Experimental results indicate that SHC improves write bandwidth by up to 5.6x compared with that of FUSE and present leading superiority on read cases.
Molecular Engineering of CoII Porphyrins with Asymmetric Architecture for Improved Electrochemical CO2 Reduction
Authors: Bao Wenwen , Huang Senhe , Tranca Diana , Feng Boxu , Qiu Feng , Rodríguez‐Hernández Fermín , Ke Changchun , Han Sheng , Zhuang Xiaodong 
Published: March 2022

AbstractThe electrochemical reduction of carbon dioxide (CO2) based on molecular catalysts has attracted more attention, owing to their well‐defined active sites and rational structural design. Metal porphyrins (PorMs) have the extended π‐conjugated backbone with different transition metals, endowing them with unique CO2 reduction properties. However, few works focus on the investigation of symmetric architecture of PorMs as well as their aggregation behavior to CO2 reduction. In this work, a series of CoII porphyrins (PorCos) with symmetric and asymmetric substituents were used as model of molecular catalysts for CO2 reduction. Owing to the electron donating effect of 2,6‐dimethylbenzene (DMB), bandgaps of the complexes became narrower with the increasing number of DMB. As electrocatalysts, all PorCos exhibited promising electrocatalytic CO2 reduction performance. Among the three molecules, asymmetric CoII porphyrin (as‐PorCo) showed the lowest onset potential of −288 mV and faradaic efficiencies exceeding 93 % at −0.6 V vs. reversible hydrogen electrode, which is highly competitive among the reported state‐of‐art porphyrin‐based electrocatalysts. The CO2 reduction performance depended on π‐π stacking between PorCo with carbon nanotubes (CNTs) and adjacent PorCos, which could be readily controlled by atomically positioned DMB in PorCo. Density functional theory calculations also suggested that the charge density between PorCo and CNT was highest due to the weak steric hindrance in as‐PorCo, providing the new insight into molecular design of catalysts for efficient electrochemical CO2 reduction.
Shared reduced ordered binary decision diagram‐based thermal‐aware network synthesis
Authors: Das Apangshu , Kumar Singh Vivek , Nath Pradhan Sambhu 
Published: March 2022

SummaryIn this work, a multi‐objective algorithm based on nondominated sorting genetic algorithm‐II (NSGA‐II) for thermal‐aware realization of a combinational logic network has been implemented. Input variable ordering of shared reduced ordered binary decision diagram (SROBDD) is done using NSGA‐II such that resulting combinational circuit generates low hotspots by suitable power density distribution. Simultaneous co‐optimization among area, power, and temperature is important in the higher levels of electronic circuit design to reduce the cooling cost. Using a multi‐objective algorithm (NSGA‐II), an effort is made to decrease the temperature by co‐optimization between the power density, area, and power simultaneously. Microelectronics Center of North Carolina (MCNC) benchmark circuits are tested using the proposed approach and an improvement of 13.65% in the silicon area and up to 10% in power dissipation, and 2.72% peak temperature reduction is reported in comparison to existing literature. HotSpot tool and Cadence Innovus are used to determine the peak temperature, actual silicon chip area, and power dissipation of algorithmic optimized solutions.
Rhodium(III) Werner Complexes with 1,2‐Diphenylethylenediamine Ligands: Syntheses, Structures, and Applications as Chiral Hydrogen Bond Donor Catalysts and Agents for Enantiomer Purity Determinations
Authors: Wegener Aaron R. , Ghosh Subrata K. , Bhuvanesh Nattamai , Reibenspies Joseph , Gladysz John A. 
Published: March 2022

AbstractReactions of RhCl3 and (S,S)‐1,2‐diphenylethylenediamine (S,S‐dpen) in DMSO at 140 °C give Λ‐[Rh(S,S‐dpen)3]3+3Cl− (Λ‐(S,S)‐43+3Cl−) in 76 % yield. When CH2Cl2/water suspensions are treated with 1.0 equiv. of Na+ B(C6F5)4− or Na+ B(3,5‐C6H3(CF3)2)4−, the mixed salts Λ‐(S,S)‐43+2Cl−B(aryl)4− can be isolated from the organic layers (95–91 %). A wide variety of mixed and non‐mixed salts involving these and other anions (BF4−, ClO4−, I−) are also prepared. The lipophilic salts are highly enantioselective catalysts for the Michael addition of dimethylmalonate to trans‐ß‐nitrostyrene (acetone, 0 °C; 92–85 % ee). The crystal structures of seven solvated salts are determined, and hydrogen bonding between the trications and anions or solvate molecules analyzed. There is a notable affinity of chloride anions for the C3 face of Λ‐(S,S)‐43+, which features three synperiplanar NH groups. Λ‐(S,S)‐43+2I−B(C6F5)4− is an excellent chiral solvating agent for determining enantiomeric purities of chiral organic molecules with hydrogen bond accepting functional groups (11 mol% (average), CDCl3).
Shock capturing with the high‐order flux reconstruction method on adaptive meshes based on p4est
Authors: Fu Hao , Xia Jian , Ma Xiuqiang 
Published: March 2022

AbstractHigh order schemes have been investigated for quite a long time, and the flux reconstruction (FR) scheme proposed by Huynh recently attracts the attention of researchers due to its simplicity and efficiency. Building the framework that bridges discontinuous Galerkin (DG) and spectral difference (SD) schemes, FR recovers DG and SD conveniently with a careful selection of parameters. In this article, FR scheme is realized based on the framework of p4est, an open source adaptive mesh refinement library. The shock capturing ability of localized Laplacian artificial viscosity and in‐cell piecewise integrated solution methods are compared. Curved boundary treatment for high order schemes is adopted. The performance of developed code is estimated in both one and two dimensions including curved boundary and shock cases, and some attractive results are obtained.
Directional selection and the evolution of breeding date in birds, revisited: Hard selection and the evolution of plasticity
Authors: Hadfield Jarrod D. , Reed Thomas E. 
Published: March 2022

AbstractThe mismatch between when individuals breed and when we think they should breed has been a long-standing problem in evolutionary ecology. Price et al. is a classic theory paper in this field and is mainly cited for its most obvious result: if individuals with high nutritional condition breed early, then the advantage of breeding early may be overestimated when information on nutritional condition is absent. Price at al.'s less obvious result is that individuals, on average, are expected to breed later than the optimum. Here, we provide an explanation of their non-intuitive result in terms of hard selection, and go on to show that neither of their results are expected to hold if the relationship between breeding date and nutrition is allowed to evolve. By introducing the assumption that the advantage of breeding early is greater for individuals in high nutritional condition, we show that their most cited result can be salvaged. However, individuals, on average, are expected to breed earlier than the optimum, not later. More generally, we also show that the hard selection mechanisms that underpin these results have major implications for the evolution of plasticity: when environmental heterogeneity becomes too great, plasticity is selected against, prohibiting the evolution of generalists.
Global factors and the transmission between United States and emerging stock markets
Authors: Naeem Muhammad Abubakr , Farid Saqib , Qureshi Fiza , Taghizadeh‐Hesary Farhad 
Published: March 2022

AbstractIn this study, we examine the influence of global factors in driving connectedness among Unite States and emerging stock markets. For this purpose, we employ widely recognized approaches of and Barunik and Krehlik to estimate connectedness among the underlying markets in time‐frequency domains. Also, we use the tests proposed by Péguin‐Feissolle and Teräsvirta to examine the impact of global factors on the transmission relationship between United States and emerging stock markets utilizing the non‐linear causality tests. The findings validate the influential role of global factors in channeling overall total spillovers between United States and emerging stock markets. However, the results for individual emerging markets show some degree of heterogeneous impact of global factors in driving connectedness across different emerging stock markets. Our robustness results also confirm the main findings. Important implications of findings are discussed for portfolio managers and policymakers.
Fenoldopam Sensitizes Primary Cilia-Mediated Mechanosensing to Promote Osteogenic Intercellular Signaling and Whole Bone Adaptation
Authors: Spasic Milos , Duffy Michael P. , Jacobs Christopher R. 
Published: March 2022

ABSTRACT
Bone cells actively respond to mechanical stimuli to direct bone formation, yet there is no current treatment strategy for conditions of low bone mass and osteoporosis designed to target the inherent mechanosensitivity of bone. Our group has previously identified the primary cilium as a critical mechanosensor within bone, and that pharmacologically targeting the primary cilium with fenoldopam can enhance osteocyte mechanosensitivity. Here, we demonstrate that potentiating osteocyte mechanosensing with fenoldopam in vitro promotes pro-osteogenic paracrine signaling to osteoblasts. Conversely, impairing primary cilia formation and the function of key ciliary mechanotransduction proteins attenuates this intercellular signaling cascade. We then utilize an in vivo model of load-induced bone formation to demonstrate that fenoldopam treatment sensitizes bones of both healthy and osteoporotic mice to mechanical stimulation. Furthermore, we show minimal adverse effects of this treatment and demonstrate that prolonged treatment biases trabecular bone adaptation. This work is the first to examine the efficacy of targeting primary cilia-mediated mechanosensing to enhance bone formation in osteoporotic animals. © 2022 American Society for Bone and Mineral Research (ASBMR).
Necroptosis‐related lncRNA to establish novel prognostic signature and predict the immunotherapy response in breast cancer
Authors: Chen Fangyue , Yang Jun , Fang Min , Wu Yanmei , Su Dongwei , Sheng Yuan 
Published: March 2022

AbstractBackgroundNecroptosis is a type of programmed cell death, and recent researches have showed that lncRNAs could regulate the process of necroptosis in multiple cancers. We tried to screen necroptosis‐related lncRNAs and investigate the immune landscape in breast cancer (BC).MethodsThe samples of breast normal and cancer tissue were acquired from TCGA and GTEx databases. A risk prognostic model was constructed based on the identified necroptosis‐related lncRNAs by Cox regression and least absolute shrinkage and selection operator (LASSO) method. Moreover, the forecast performance of this model was verified and accredited by synthetic approach. Subsequently, an accurate nomogram was constructed to predict the prognosis of BC patients. The biological differences were investigated through GO, GSEA, and immune analysis. The immunotherapy response was estimated through tumor mutation burden (TMB) and tumor immune dysfunction and exclusion (TIDE) score.ResultsA total of 251 necroptosis‐related lncRNAs were identified by differential coexpression analysis, and SH3BP5‐AS1, AC012073.1, AC120114.1, LINC00377, AL133467.1, AC036108.3, and AC020663.2 were involved in the risk model, which had an excellent concordance with the prediction. The pathway analyses showed that immune‐related pathways were relevant to the necroptosis‐related lncRNAs risk model. And the risk score was significantly correlated with immune cell infiltration, as well as the ESTIMATE score. Most notably, the patients of higher risk score were characterized with increased TMB and decreased TIDE score, indicating that these patients showed better immune checkpoint blockade response.ConclusionThese findings were conducive to understand the function of necroptosis‐related lncRNAs in BC and provide a potential promising therapeutic strategy for BC.
Characterization of the significant decline in humoral immune response six months post‐SARS‐CoV‐2 mRNA vaccination: A systematic review
Authors: Notarte Kin Israel , Guerrero‐Arguero Israel , Velasco Jacqueline Veronica , Ver Abbygail Therese , Santos de Oliveira Maria Helena , Catahay Jesus Alfonso , Khan Md. Siddiqur Rahman , Pastrana Adriel , Juszczyk Grzegorz , Torrelles Jordi B. , Lippi Giuseppe , Martinez‐Sobrido Luis , Henry Brandon Michael 
Published: March 2022

AbstractAccumulating evidence shows a progressive decline in the efficacy of coronavirus disease 2019 (COVID‐19) (severe acute respiratory syndrome coronavirus 2 [SARS‐CoV‐2]) messenger RNA (mRNA) vaccines such as Pfizer‐BioNTech (mRNA BNT161b2) and Moderna (mRNA‐1273) in preventing breakthrough infections due to diminishing humoral immunity over time. Thus, this review characterizes the kinetics of anti‐SARS‐CoV‐2 antibodies after the second dose of a primary cycle of COVID‐19 mRNA vaccination. A systematic search of the literature was performed and a total of 18 articles (N = 15 980 participants) were identified and reviewed. The percent difference of means of reported antibody titers was then calculated to determine the decline in humoral response after the peak levels postvaccination. Findings revealed that the peak humoral response was reached at 21–28 days after the second dose, after which serum levels progressively diminished at 4–6‐month postvaccination. Additionally, results showed that regardless of age, sex, serostatus, and presence of comorbidities, longitudinal data reporting antibody measurement exhibited a decline of both anti‐receptor binding domain immunoglobulin G (IgG) and anti‐spike IgG, ranging from 94% to 95% at 90–180 days and 55%–85% at 140–160 days, respectively, after the peak antibody response. This suggests that the rate of antibody decline may be independent of patient‐related factors and peak antibody titers but mainly a function of time and antibody class/molecular target. Hence, this study highlights the necessity of more efficient vaccination strategies to provide booster administration in attenuating the effects of waning immunity, especially in the appearance of new variants of concerns.
Reanalysis‐driven multi‐RCM high‐resolution simulation of precipitation within CORDEX East Asia Phase II
Authors: Tang Jianping , Xiao Yuxin , Hui Pinhong , Lu Yutong , Yu Ke 
Published: March 2022

AbstractUnder the Coordinated Regional Downscaling Experiment‐East Asia second phase (CORDEX‐EA‐II) framework, the performances of three regional climate models (RCMs), including Weather Research and Forecasting (WRF) model, RegCM4 and Consortium for Small‐Scale Modelling model in Climate Mode (CCLM), in simulating the climatic distribution, diurnal variation and extremes of precipitation during 1989–2009 are evaluated. The RCMs are driven by the ERA‐Interim reanalysis and the evaluation is based on both the gridded gauge‐based and the satellite‐derived precipitation data. In general, the RCMs can reproduce the spatial pattern of the mean daily precipitation, with the spatial correlations (SCORs) larger than 0.66, and CCLM has the lowest root‐mean‐square error over East Asia. For the diurnal cycle of precipitation, WRF outperforms the other two RCMs despite the peak time about 3 hr ahead in some areas. RegCM4 overestimates the amplitude of the diurnal curve, and CCLM has limited ability to simulate the diurnal variation over most areas. All the three RCMs can reproduce the spatial patterns of the extreme indices, with the SCORs larger than 0.57. WRF and CCLM perform the best for the frequency of wet days (R1mm) and moderate rain (R20mm), respectively. The intensity indices are overestimated over most land areas, with relatively higher SCORs in WRF and relatively lower biases in RegCM4. The consecutive wet days (CWD) can be well simulated by WRF and CCLM; however, RegCM4 overestimates it over most regions in East Asia. The overestimation of the extreme intensity and frequency indices may be related to the higher water vapour content and the weaker water vapour divergence in the lower layer, as well as the higher mid‐layer geopotential height, especially in CCLM.