A physical retrieval algorithm has been developed for deriving the layered precipitable water vapor (LPWs) product from infrared radiances of the Advanced Geosynchronous Radiation Imager (AGRI) ...onboard FengYun-4A (FY-4A), the first of the new generation of Chinese geostationary weather satellites (FengYun-4, or FY-4 Series). The FY-4A AGRI LPWs are evaluated with different types of reference datasets based on Quality Control System (QCS), including those from Himawari-8 AHI (Advanced Himawari Imager), MODIS (Moderate Resolution Imaging Spectroradiometer), Radiosonde, ERA5 (European Centre for Medium-Range Weather Forecasts Reanalysis v5), NCEP (National Centers for Environmental Prediction) reanalysis and CMA (China Meteorological Administration) forecast product from global medium range numerical weather prediction (NWP) system. QCS is one of the important components of FY-4A ground segment, which mainly focuses on the satellite products’ evaluation and validation. It is found that the AGRI LPW product has a good agreement with different evaluating sources and the quality is favorable and stable. With the capability of frequent (5-min interval) observations over the East Asia and Western Pacific regions, the AGRI LPW products can be used to investigate the atmospheric temporal and spatial variations in the pre-landfall environment for typhoons. The QCS is a useful tool to monitor, evaluate, and validate the AGRI LPW products.
Through several decades of development, global sensitivity analysis has been developed as a very useful guide tool for assessing scientific models and has gained pronounced attention in environmental ...science. However, standard global sensitivity analysis aims at measuring the contribution of input variables to model output uncertainty on average by investigating their full distribution ranges, but does not investigate the contribution of specific ranges. To deal with this problem, researchers have developed several regional sensitivity analysis techniques such as the contribution to sample mean and variance (CSM and CSV) plots. In this paper, a moment-independent regional sensitivity analysis technique called contribution to delta indices (CDI) plot is developed for assessing the effect of a specific range of an individual input to the uncertainty of model output. The CDI plot can be obtained with the same set of samples used for computing the CSM and CSV. Compared with the CSM and CSV, the CDI plot uses the probability density function shift of model output to describe the uncertainty instead of the mean and variance, thus it is moment-independent. An analytical linear model, the Ishigami function and an environmental model are employed to test the proposed RSA technique.
•Contribution to delta indices (CDI) plot is developed.•CDI plot measures the contribution of specific range of inputs to output uncertainty.•The proposed technique is moment-independent.•Only a set of samples are needed for implementing the CDI plot.•The proposed technique is applied to an environmental model.
Compared with the global analysis, the regional analysis can offer more comprehensive and more detail information with an input variable fixed in an interval. Existing validation metrics mostly focus ...on the global discrepancy between the observations and the computer models. To further measure the difference in detail, the concept of regional validation was proposed in this work. To make regional validation specific and easily understandable, two existing validation metrics-the area metric and the G metric were applied. The contribution to whole validation (CWV) metric was proposed to depict the relationship between the proposed regional validation and the initial whole scale validation. At last, an example was employed to demonstrate the rationality and necessity of the regional validation.
Computational models have been widely applied to simulate complex physical phenomena because of rapid development of computers' abilities and inexecutable conditions of the experiments. Validating ...the effectiveness of computational models is then essential and significant. Existing validation metrics focusing on a single response may cause confusing results when they are applied for multiple responses simultaneously. The target of this work is to validate computational models with multiple responses via the factor analysis method by considering both the uncertainty and correlation of the multiple responses. Factor analysis aims to explain the correlated multi-dimensional variables with fewer common factors and the latter then can describe the main information the former containing. Briefly, factor analysis has a favorable ascendency--dimensionality reduction, which makes multiple responses validation easy to implement. The proposed method is based on the factor analysis and the concept of "area metric" for validating a single response, which avoids comparing the joint distribution of the computational models and that of the experimental observations. It is applicable for validating multiple responses both at a single validation site and at multiple validation sites. Both numerical example and engineering example are employed to demonstrate the rationality and necessity of the proposed methodology.
BackgroundDespite recent advances in T-cell engager based multiple myeloma therapies, high rate of cytokine release syndrome (CRS) and severe neurotoxicity remains a challenge in clinic. EMB-06 is a ...novel 2+2 BCMA×CD3 T-Cell engaging bispecific antibody developed based on the EpimAb’s proprietary Fabs-In-Tandem-Immunoglobulin (FIT-Ig®) platform. Differentiated from existing T-cell engagers, EMB-06 comprises tetravalent binding domains in cis-configuration and proprietary anti-CD3 arms with optimized affinity. It induced modest levels of cytokine release yet retained robust anti-tumor activity in preclinical studies. Here we report the initial results from an ongoing multicenter, first-in-human, Phase I study of EMB-06 in relapsed or refractory multiple myeloma (RRMM).MethodsThe Phase I study evaluates escalating doses of once weekly IV administrations of EMB-06 in patients (pts) with RRMM who have failed or are intolerant to standard therapies. Dose escalation was guided by the Bayesian optimal interval (BOIN) design. Primary objectives were to assess safety, tolerability, and determine the MTD and/or RP2Ds. Secondary objectives were to assess pharmacokinetics (PK), pharmacodynamics (PD), immunogenicity, and preliminary anti-tumor activities.ResultsAs of Aug 28, 2023, 33 pts had been treated with EMB-06 at 0.2mg to 200mg. Median age was 66 y (46–82). Median prior lines of therapies were 3 (2–6) and 26 (79%) pts were refractory to the most recent line of therapy. Treatment-related AEs (TRAEs) were reported in 20 (61%) pts, with Gr ≥3 occurring in 7 (21%) pts. The most common TRAEs include ALT increase (18%), leukopenia (18%), ALP increase (15%), neutropenia (15%), anemia (12%), AST increase (12%), GGT increase (12%), lymphopenia (12%) and CRS (12%). All CRS were Grade 1. Only 1 patient experienced treatment related neurotoxicity (Gr.1 paresthesia). One DLT (pneumonia, cardiac failure, creatinine increased and hepatic insufficiency) was observed at 60mg cohort. EMB-06 shows dose proportional increase in PK exposure across 0.2–120 mg, and the median half-life after single dosing is 4.4 days. PD activity (T cell redistribution and activation along with transient release of low-level cytokines) was observed at doses ≥0.6mg. The ORR was 29% (9/31) among 31 response evaluable pts. Of the 5 evaluable pts treated with doses ≥120mg, the ORR was 100% (1 CR, 2 VGPR, 2 PR).ConclusionsEMB-06 demonstrated a differentiated safety profile in RRMM pts with exceptionally low CRS and neurotoxicity rates so far. An initial ORR of 100% has been observed at doses ≥120mg. Updated data will be shared at the meeting.Trial RegistrationThe clinical trial was registered with www.clinicaltrials.gov (NCT04735575).Ethics ApprovalThe trial was done according to Good Clinical Practice and the Declaration of Helsinki. The protocol and amendments were approved by the institutional review board or ethics committee at each site. And all participants gave informed consent before taking part in the trial. The name of the ethics committee(s) or institutional review board(s), the number/ID of the approval(s) are as follow:Epworth health – No. 2020-12-1350Sunshine Coast Haematology and Oncology Clinic- No. 2020-12-1350-AAOne Clinical Research - No. 2020-12-1350-AB Ethics Committee of Ruijin Hospital Affiliated to Shanghai Jiaotong University School Of Medicine-No. 2021- 73 Henan Cancer Hospital Medical Science Research Ethics Committee-No. 2021-381-002Clinical Trial Ethics Committee of Huazhong University of Science and Technology-No. 2021-218Ethics Committee of the First Affiliated Hospital, School Of Medicine, Zhejiang University-No. 2021-627 Ethics Committee of Beijing Jishuitan Hospital-No. 20210902-01Peking University Third Hospital Medical Science Research Ethics Committee-No.2022-220-02Ethics Committee of Guangdong Provincial People’s Hospital-No. YW2023-011-02ConsentWritten informed consent was obtained from the patient for publication of this abstract and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.
•Nitrate promoted AGS formation but also caused disintegration.•Nitrate affected AGS formation and disintegration by NO, c-di-GMP and EPS.•The denitrification-derived NO regulated c-di-GMP ...level.•Nitrate favored the enrichment of denitrifiers and EPS producing microbes.•c-di-GMP regulated amino acids and sugar metabolites for EPS biosynthesis.
As a promising wastewater treatment technology, aerobic granular sludge (AGS) process is still hindered by slow granule formation and easy disintegration in the application. While nitrate, one of the target pollutants in wastewater, showed a potential effect on AGS granulation process. Herein, this study attempted to reveal the role of nitrate in AGS granulation. By adding exogenous nitrate (10 mg L−1), the AGS formation was markedly improved and accomplished at 63 d, while the control group achieved AGS formation at 87 d. However, a disintegration was observed under a long-term nitrate feeding. A positive correlation was observed among granule size, extracellular polymeric substances (EPS) and intracellular c-di-GMP level in both formation and disintegration phases. The subsequent static biofilm assays indicated that nitrate might upregulate c-di-GMP via denitrification-derived NO, and c-di-GMP further upregulated EPS, thereby promoting AGS formation. However, excessive NO probably caused disintegration by downregulating c-di-GMP and EPS. Microbial community showed that nitrate favored the enrichment of denitrifiers and EPS producing microbes, which were responsible for the regulation of NO, c-di-GMP and EPS. Metabolomics analysis showed that amino acid metabolism was the most affected metabolism by nitrate. Some amino acids, such as Arg, His and Asp, were upregulated in the granule formation phase and downregulated in the disintegration phase, indicating the potential contribution to EPS biosynthesis. This study provides metabolic insight into how nitrate promotes/inhibits granulation, which may contribute to unwrapping the mystery of granulation and overcoming the limitations of AGS application.
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Quadriaxial non-crimp fabric (QNCF) composites are increasingly being used as primary structural materials in aircraft and automotive applications. Predicting the mechanical properties of QNCF lamina ...is more complicated compared with that of unidirectional (UD) composites, because of the knitting connection of different plies. In this study, to analyze the stiffness and strength of the QNCF composites, a novel modeling strategy for the meso-scale features is presented based on the semi-laminar assumption. Following the view of the mechanical properties of single composite lamina, the complex QNCF layer is decomposed into individual plies. Three different representative unit cells along fiber direction are selected to predict the mechanical performance of QNCF, including in-plane stiffness, damage initiation, and stiffness degradation. To validate the developed modeling strategy, the predictions are compared with existing experimental results, where a good agreement is presented on the prediction of in-plane stiffness and strength. Furthermore, the effect of in-plane fiber distortion, induced by the stitching yarn on the mechanical properties, is studied.
Two revised regional importance measures （RIMs）, that is, revised contribution to variance of sample mean （RCVSM） and re- vised contribution to variance of sample variance （RCVSV）, are defined herein ...by using the revised means of sample mean and sample variance, which vary with the reduced range of the epistemic parameter. The RCVSM and RCVSV can be com- puted by the same set of samples, thus no extra computational cost is introduced with respect to the computations of CVSM and CVSV. From the plots of RCVSM and RCVSV, accurate quantitative information on variance reductions of sample mean and sample variance can be read because of reduced upper bound of the range of the epistemic parameter. For general form of quadratic polynomial output, the analytical solutions of the original and the revised RIMs are given. Numerical example is em- ployed and results demonstrate that the analytical results are consistent and accurate. An engineering example is applied to tes- tify the validity and rationality of the revised RIMs, which can give instructions to the engineers about how to reduce variance of sample mean and sample variance by reducing the range of epistemic parameters.
Mathematical and computational models with correlated multivariate output are commonly used for risk assessment and decision support in engineering. Traditional methods for sensitivity analysis of ...the model with scalar output fail to provide satisfactory results for this multivariate case. In this work, we introduce a new sensitivity index which looks at the influence of input uncertainty on the entire distribution of the multivariate output without reference to a specific moment of the output. The definition of the new index is based on the multivariate probability integral transformation (PIT), which can take into account both of the uncertainties and the correlations among multivariate output. The mathematical properties of the proposed sensitivity index are discussed and its differences with the sensitivity indices previously introduced in the literature are highlighted. Two numerical examples and a rotating shaft model of an aircraft wing are employed to illustrate the validity and potential benefits of the new sensitivity index.
•A new sensitivity index for models with multivariate output is presented.•The new index can consider both uncertainties and correlations of multivariate output.•The mathematical properties of the new index are derived.•The advantages of the new index with respect to the existing ones are highlighted.
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