Pyrazole compound BPR1P0034 with potent and selective anti-influenza virus activity

<p>Abstract</p> <p>Background</p> <p>Influenza viruses are a major cause of morbidity and mortality around the world. More recently, a swine-origin influenza A (H1N1) virus that is spreading via human-to-human transmission has become a serious public concern. Although vaccination is the primary strategy for preventing infections, influenza antiviral drugs play an important role in a comprehensive approach to controlling illness and transmission. In addition, a search for influenza-inhibiting drugs is particularly important in the face of high rate of emergence of influenza strains resistant to several existing influenza antivirals.</p> <p>Methods</p> <p>We searched for novel anti-influenza inhibitors using a cell-based neutralization (inhibition of virus-induced cytopathic effect) assay. After screening 20,800 randomly selected compounds from a library from ChemDiv, Inc., we found that BPR1P0034 has sub-micromolar antiviral activity. The compound was resynthesized in five steps by conventional chemical techniques. Lead optimization and a structure-activity analysis were used to improve potency. Time-of-addition assay was performed to target an event in the virus life cycle.</p> <p>Results</p> <p>The 50% effective inhibitory concentration (IC₅₀) of BPR1P0034 was 0.42 ± 0.11 μM, when measured with a plaque reduction assay. Viral protein and RNA synthesis of A/WSN/33 (H1N1) was inhibited by BPR1P0034 and the virus-induced cytopathic effects were thus significantly reduced. BPR1P0034 exhibited broad inhibition spectrum for influenza viruses but showed no antiviral effect for enteroviruses and echovirus 9. In a time-of-addition assay, in which the compound was added at different stages along the viral replication cycle (such as at adsorption or after adsorption), its antiviral activity was more efficient in cells treated with the test compound between 0 and 2 h, right after viral infection, implying that an early step of viral replication might be the target of the compound. These results suggest that BPR1P0034 targets the virus during viral uncoating or viral RNA importation into the nucleus.</p> <p>Conclusions</p> <p>To the best of our knowledge, BPR1P0034 is the first pyrazole-based anti-influenza compound ever identified and characterized from high throughput screening to show potent (sub-μM) antiviral activity. We conclude that BPR1P0034 has potential antiviral activity, which offers an opportunity for the development of a new anti-influenza virus agent.</p

Longitudinal Evaluation of an N-Ethyl-N-Nitrosourea-Created Murine Model with Normal Pressure Hydrocephalus

Normal-pressure hydrocephalus (NPH) is a neurodegenerative disorder that usually occurs late in adult life. Clinically, the cardinal features include gait disturbances, urinary incontinence, and cognitive decline.Herein we report the characterization of a novel mouse model of NPH (designated p23-ST1), created by N-ethyl-N-nitrosourea (ENU)-induced mutagenesis. The ventricular size in the brain was measured by 3-dimensional micro-magnetic resonance imaging (3D-MRI) and was found to be enlarged. Intracranial pressure was measured and was found to fall within a normal range. A histological assessment and tracer flow study revealed that the cerebral spinal fluid (CSF) pathway of p23-ST1 mice was normal without obstruction. Motor functions were assessed using a rotarod apparatus and a CatWalk gait automatic analyzer. Mutant mice showed poor rotarod performance and gait disturbances. Cognitive function was evaluated using auditory fear-conditioned responses with the mutant displaying both short- and long-term memory deficits. With an increase in urination frequency and volume, the mutant showed features of incontinence. Nissl substance staining and cell-type-specific markers were used to examine the brain pathology. These studies revealed concurrent glial activation and neuronal loss in the periventricular regions of mutant animals. In particular, chronically activated microglia were found in septal areas at a relatively young age, implying that microglial activation might contribute to the pathogenesis of NPH. These defects were transmitted in an autosomal dominant mode with reduced penetrance. Using a whole-genome scan employing 287 single-nucleotide polymorphic (SNP) markers and further refinement using six additional SNP markers and four microsatellite markers, the causative mutation was mapped to a 5.3-cM region on chromosome 4.Our results collectively demonstrate that the p23-ST1 mouse is a novel mouse model of human NPH. Clinical observations suggest that dysfunctions and alterations in the brains of patients with NPH might occur much earlier than the appearance of clinical signs. p23-ST1 mice provide a unique opportunity to characterize molecular changes and the pathogenic mechanism of NPH

A Hybrid ECOM Model for Solar Radiation Pressure Effect on GPS Reference Orbit Derived by Orbit Fitting Technique

A hybrid ECOM (Empirical CODE Orbit Model) solar radiation pressure (SRP) model, which is termed ECOMC in this work, is proposed for global navigation satellite system (GNSS) orbit modeling. The ECOMC is mainly parameterized by both ECOM1 and ECOM2 models. The GNSS orbit mainly serves as a reference datum not only for its ranging measurement but also for the so-called precise point positioning (PPP) technique. Compared to a complex procedure of orbit determination with real tracking data, the so-called orbit fitting technique simply uses satellite positions from GNSS ephemeris as pseudo-observations to estimate the initial state vector and SRP parameters. The accuracy of the reference orbit is mainly dominated by the SRP, which is usually handled by either ECOM1 or ECOM2. However, the reference orbit derived by ECOM1 produces periodic variations on orbit differences with respect to International GNSS Service (IGS) final orbit for GPS IIR satellites. Such periodic variations are removed from a reference orbit formed using the ECOM2 model, which, however, yields large cross-track orbit errors for the IIR and IIF satellites. Such large errors are attributed to the fact that the ECOM2 intrinsically lacks 1 cycle per revolution (CPR) terms, which stabilize the estimations of the even-order CPR terms in the satellite-Sun direction when the orbit fitting is used. In comparison, a reference orbit constructed with the ECOMC model is free of both the periodic variations from the ECOM1 and the large cross-track orbit errors from the ECOM2. The above improvements from the ECOMC are associated with (1) the even CPR terms removing the periodic variations and (2) the 1 CPR terms compensating for the force mismodeling at &#8710;u = 90&deg; and 270&deg;, where the &#8710;u is the argument of the latitude of the satellite with respect to the Sun. The parameter correlation analysis also presents that the direct SRP estimation is sensitive to the 1 and 2 CPR terms in the ECOMC case. In addition, the root-mean-square (RMS) of orbit difference with respect to IGS orbit is improved by ~40%, ~10%, and ~50% in the radial, along-track, and cross-track directions, respectively, when the SRP model is changed from the ECOM2 to the ECOMC. The orbit accuracy is assessed through orbit overlaps at day boundaries. The accuracy improvements of the ECOMC-derived orbit over the ECOM2-derived orbit in the radial, along-track, and cross-track directions are 13.2%, 14.8%, and 42.6% for the IIF satellites and 7.4%, 7.7%, and 35.0% for the IIR satellites. The impact of the reference orbit using the three models on the PPP is assessed. The positioning accuracy derived from the ECOMC is better than that derived from the ECOM1 and ECOM2 by approximately 13% and 20%, respectively. This work may serve as a reference for forming the GNSS reference orbit using the orbit fitting technique with the ECOMC SRP model

Letter from the guest editors of the topical collection on satellite orbit determination

Copyright: Copyright 2021 Elsevier B.V., All rights reserved.Space Engineerin

Terrestrial Water Storage in African Hydrological Regimes Derived from GRACE Mission Data: Intercomparison of Spherical Harmonics, Mass Concentration, and Scalar Slepian Methods

Spherical harmonics (SH) and mascon solutions are the two most common types of solutions for Gravity Recovery and Climate Experiment (GRACE) mass flux observations. However, SH signals are degraded by measurement and leakage errors. Mascon solutions (the Jet Propulsion Laboratory (JPL) release, herein) exhibit weakened signals at submascon resolutions. Both solutions require a scale factor examined by the CLM4.0 model to obtain the actual water storage signal. The Slepian localization method can avoid the SH leakage errors when applied to the basin scale. In this study, we estimate SH errors and scale factors for African hydrological regimes. Then, terrestrial water storage (TWS) in Africa is determined based on Slepian localization and compared with JPL-mascon and SH solutions. The three TWS estimates show good agreement for the TWS of large-sized and humid regimes but present discrepancies for the TWS of medium and small-sized regimes. Slepian localization is an effective method for deriving the TWS of arid zones. The TWS behavior in African regimes and its spatiotemporal variations are then examined. The negative TWS trends in the lower Nile and Sahara at −1.08 and −6.92 Gt/year, respectively, are higher than those previously reported

Metabolic Volumetric Parameters in 11C-Choline PET/MR Are Superior PET Imaging Biomarkers for Primary High-Risk Prostate Cancer

Purpose. Positron emission tomography/magnetic resonance imaging (PET/MRI) can facilitate the use of noninvasive imaging biomarkers in clinical prostate cancer staging. Although multiparametric MRI is a widely used technique, the clinical value of simultaneous PET imaging remains unclear. This study aimed at investigating this issue. Methods. Between January 2015 and December 2016, 31 high-risk prostate cancer patients underwent 11C-choline PET/MRI for staging purposes. Clinical characteristics and imaging parameters, including the standardized uptake value (SUV) and metabolic volumetric parameters from PET imaging; apparent diffusion coefficient (ADC) values from diffusion-weighted imaging; and volume transfer rate constant (Ktrans), reflux rate constant (Kep), and initial area under curve (iAUC) in 60 seconds from dynamic contrast-enhanced (DCE) MRI were analyzed. Results. 11C-Choline PET imaging parameters were significantly correlated with prostate-specific antigen (PSA) levels, and metabolic volumetric parameters, including metabolic tumor volume (MTV) and uptake volume product (UVP), showed significant correlations with other MRI parameters. In our cohort analysis, the PET/MRI parameters UVP/minimal ADC value (ADCmin) and kurtosis of Kep (Kepkur)/ADCmin were significant predictors for progression-free survival (PFS) (HR = 1.01, 95% CI: 1.00–1.02, p=0.031 and HR = 1.09, 95% CI: 1.02–1.16, p=0.009, respectively) in multivariate Cox regression analysis. High UVP/ADCmin and Kepkur/ADCmin values were significantly associated with shorter PFS. Conclusions. Metabolic volumetric parameters such as MTV and UVP can be routinely used as PET imaging biomarkers to add prognostic value and show better correlations in combination with MR imaging parameters in high-risk prostate cancer patients undergoing 11C-choline PET/MRI