A Compensation Method for the Geomagnetic Measurement Error of an Underwater Ship-Borne Magnetometer Based on Constrained Total Least Squares.

When magnetic matching aided navigation is applied to an underwater vehicle, the magnetometer must be installed inside the vehicle, considering the navigation safety and concealment of the underwater vehicle. Then, the interference magnetic field will seriously affect the accuracy of geomagnetic field measurement, which directly affects the accuracy of geomagnetic matching aided navigation. Therefore, improving the accuracy of geomagnetic measurements inside the vehicle through error compensation has become one of the most difficult problems that requires an urgent solution in geomagnetic matching aided navigation. In order to solve this problem, this paper establishes the calculation model of the internal magnetic field of the underwater vehicle and the geomagnetic measurement error model of the ship-borne magnetometer. Then, a compensation method for the geomagnetic measurement error of the ship-borne magnetometer, based on the constrained total least square method, is proposed. To verify the effectiveness of the method proposed in this paper, a simulation experiment of geomagnetic measurement and compensation of a ship-borne three-axis magnetometer was constructed. Among them, to be closer to the real situation, a combination of the geomagnetism model, the elliptic shell model and the magnetic dipole model was used to simulate the internal magnetic field of the underwater vehicle. The experimental results indicated that the root mean square error of geomagnetic measurement in an underwater vehicle was less than 5 nT after compensation, and the accuracy of geomagnetic measurement met the requirements of geomagnetic matching aided navigation.

Discovery of Novel Cinnamic Acid Derivatives as Fungicide Candidates.

Structural diversity derivatization from natural products is an important and effective method of discovering novel green pesticides. Cinnamic acids are abundant in plants, and their unparalleled structures endow them with various excellent biological activities. A series of novel cinnamic oxime esters were designed and synthesized to develop high antifungal agrochemicals. The antifungal activity, structure-activity relationship, and action mechanism were systematically studied. Compounds 7i, 7u, 7v, and 7x exhibited satisfactory activity against Gaeumannomyces graminis var. tritici, with inhibition rates of ≥90% at 50 µg/mL. Compounds 7z and 7n demonstrated excellent activities against Valsa mali and Botrytis cinerea, with median effective concentration (EC50) values of 0.71 and 1.41 µg/mL, respectively. Compound 7z exhibited 100% protective and curative activities against apple Valsa canker at 200 µg/mL. The control effects of 7n against gray mold on tomato fruits and leaves were all >96%, exhibiting superior or similar effects to those of the commercial fungicide boscalid. Furthermore, the quantitative structure-activity relationship was established to guide the further design of higher-activity compounds. The preliminary results on the action mechanism revealed that 7n treatment could disrupt the function of the nucleus and mitochondria, leading to reactive oxygen species accumulation and cell membrane damage. Its primary biochemical mechanism may be inhibiting fungal ergosterol biosynthesis. The novel structure, simple synthesis, and excellent activity of cinnamic oxime esters render them promising potential fungicides.

Metabolite Bioanalysis in Drug Development: Recommendations from the IQ Consortium Metabolite Bioanalysis Working Group.

The intent of this perspective is to share the recommendations of the International Consortium for Innovation and Quality in Pharmaceutical Development Metabolite Bioanalysis Working Group on the fit-for-purpose metabolite bioanalysis in support of drug development and registration. This report summarizes the considerations for the trigger, timing, and rigor of bioanalysis in the various assessments to address unique challenges due to metabolites, with respect to efficacy and safety, which may arise during drug development from investigational new drug (IND) enabling studies, and phase I, phase II, and phase III clinical trials to regulatory submission. The recommended approaches ensure that important drug metabolites are identified in a timely manner and properly characterized for efficient drug development.

Efficacy and toxic action of the natural product natamycin against Sclerotinia sclerotiorum.

BACKGROUND: Sclerotinia stem rot caused by Sclerotinia sclerotiorum seriously endangers oilseed rape production worldwide, and the occurrence of fungicide-resistant mutants of S. sclerotiorum leads to control decline. Thus, it is critical to explore new green substitutes with different action mechanisms and high antifungal activity. Herein, the activity and the action mechanism of natamycin against S. sclerotiorum were evaluated. RESULTS: Natamycin showed potent inhibition on the mycelial growth of S. sclerotiorum, and half-maximal effective concentration (EC50 ) values against 103 S. sclerotiorum strains ranged from 0.53 to 4.04 µg/mL (mean 1.44 µg/mL). Natamycin also exhibited high efficacy against both carbendazim- and dimethachlone-resistant strains of S. sclerotiorum on detached oilseed rape leaves. No cross-resistance was detected between natamycin and carbendazim. Natamycin markedly disrupted hyphal form, sclerotia formation, integrity of the cell membrane, and reduced the content of oxalic acid and ergosterol, whereas it increased the reactive oxygen species (ROS) and malondialdehyde content. Interestingly, exogenous addition of ergosterol could reduce the inhibition of natamycin against S. sclerotiorum. Importantly, natamycin significantly inhibited expression of the Cyp51 gene, which is contrary to results for the triazole fungicide flusilazole, indicating a different action mechanism from triazole fungicides. CONCLUSION: Natamycin is a promising effective candidate for the resistance management of S. sclerotiorum. © 2023 Society of Chemical Industry.

Comparison of Perioperative Safety of Carotid Artery Stenting and Endarterectomy in the Treatment of Carotid Artery Stenosis: A Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: Current management guidelines for the treatment of carotid stenosis are controversial. We performed this meta-analysis to evaluate the perioperative safety of carotid artery stenting (CAS) and endarterectomy. METHODS: We systematically searched EMBASE, PubMed, Web of Science, and the Cochrane Library from inception to November 10, 2022, for randomized controlled trials that compared CAS with carotid endarterectomy (CEA) among patients with carotid stenosis. The analyzed outcomes mainly included stroke, death, myocardial infarction (MI), cranial nerve palsy, the cumulative incidence of mortality, stroke, or MI and the cumulative incidence of death or stroke in the perioperative periods. The risk ratio (RR) and 95% confidence interval (95% CI) were calculated and pooled. Subgroup analyses were based on whether patients were symptomatic or asymptomatic. We assessed the certainty of evidence using the Grading of Recommendations Assessment, Development and Evaluation framework. RESULTS: Seventeen randomized controlled trials with 12,277 participants (6514 and 5763 in the CAS and CEA groups, respectively) were included. Pooled analysis demonstrated that compared with CEA, CAS was associated with decreased risks of perioperative MI (RR = 0.47, 95% CI = 0.29∼0.77) and perioperative cranial nerve palsy (RR = 0.02, 95% CI = 0.01∼0.06) but higher risks of perioperative stroke (RR = 1.48, 95% CI = 1.18∼1.87) and cumulative incidence of death or stroke (RR = 1.52, 95% CI = 1.20∼1.93). CONCLUSIONS: The perioperative safety was equivalent between CAS and CEA. However, CEA may be preferred when considering both procedural safety and long-term efficacy in preventing recurrent stroke.

2022 White Paper on Recent Issues in Bioanalysis: ICH M10 BMV Guideline & Global Harmonization; Hybrid Assays; Oligonucleotides & ADC; Non-Liquid & Rare Matrices; Regulatory Inputs (Part 1A - Recommendations on Mass Spectrometry, Chromatography and Sample Preparation, Novel Technologies, Novel Modalities, and Novel Challenges, ICH M10 BMV Guideline & Global Harmonization Part 1B - Regulatory Agencies' Inputs on Regulated Bioanalysis/BMV, Biomarkers/CDx/BAV, Immunogenicity, Gene & Cell Therapy and Vaccine).

The 16th Workshop on Recent Issues in Bioanalysis (16th WRIB) took place in Atlanta, GA, USA on September 26-30, 2022. Over 1000 professionals representing pharma/biotech companies, CROs, and multiple regulatory agencies convened to actively discuss the most current topics of interest in bioanalysis. The 16th WRIB included 3 Main Workshops and 7 Specialized Workshops that together spanned 1 week in order to allow exhaustive and thorough coverage of all major issues in bioanalysis, biomarkers, immunogenicity, gene therapy, cell therapy and vaccines. Moreover, in-depth workshops on the ICH M10 BMV final guideline (focused on this guideline training, interpretation, adoption and transition); mass spectrometry innovation (focused on novel technologies, novel modalities, and novel challenges); and flow cytometry bioanalysis (rising of the 3rd most common/important technology in bioanalytical labs) were the special features of the 16th edition. As in previous years, WRIB continued to gather a wide diversity of international, industry opinion leaders and regulatory authority experts working on both small and large molecules as well as gene, cell therapies and vaccines to facilitate sharing and discussions focused on improving quality, increasing regulatory compliance, and achieving scientific excellence on bioanalytical issues. This 2022 White Paper encompasses recommendations emerging from the extensive discussions held during the workshop and is aimed to provide the bioanalytical community with key information and practical solutions on topics and issues addressed, in an effort to enable advances in scientific excellence, improved quality and better regulatory compliance. Due to its length, the 2022 edition of this comprehensive White Paper has been divided into three parts for editorial reasons. This publication (Part 1A) covers the recommendations on Mass Spectrometry and ICH M10. Part 1B covers the Regulatory Agencies' Inputs on Bioanalysis, Biomarkers, Immunogenicity, Gene & Cell Therapy and Vaccine. Part 2 (LBA, Biomarkers/CDx and Cytometry) and Part 3 (Gene Therapy, Cell therapy, Vaccines and Biotherapeutics Immunogenicity) are published in volume 15 of Bioanalysis, issues 15 and 14 (2023), respectively.

LC-MS/MS Bioanalysis of Radioligand Therapeutic Drug Candidate for Preclinical Toxicokinetic Assessment.

Radioligand therapy (RLT) has gained significant momentum in recent years in the diagnosis, treatment, and monitoring of cancers. In preclinical development, the safety profile of RLT drug candidate(s) is investigated at relatively low dose levels using the cold (non-radioactive, e.g., 175Lu) ligand as a surrogate of the hot (radioactive, e.g., 177Lu) one in the "ligand-linker-chelator" complex. The formulation of the test article used in preclinical safety studies contains a mixture of free ligand (i.e., ligand-linker-chelator without metal) and cold ligand (i.e., ligand-linker-chelator with non-radioactive metal) in a similar molar ratio as seen under the manufacturing conditions for the RLT drug for clinical use, where only a fraction of free ligand molecules chelate the radioactive metal to form a hot ligand. In this very first report of LC-MS/MS bioanalysis of RLT molecules in support of a regulated preclinical safety assessment study, a highly selective and sensitive LC-MS/MS bioanalytical method was developed for the simultaneous determination of free ligand (NVS001) and cold ligand (175Lu-NVS001) in rat and dog plasma. Several unexpected technical challenges in relation to LC-MS/MS of RLT molecules were successfully addressed. The challenges include poor assay sensitivity of the free ligand NVS001, formation of the free ligand (NVS001) with endogenous metal (e.g., potassium), Ga loss from the Ga-chelated internal standard during sample extraction and analysis, "instability" of the analytes at low concentrations, and inconsistent IS response in the extracted plasma samples. The methods were validated according to the current regulatory requirements in a dynamic range of 0.5-250 ng/mL for both the free and cold ligands using a 25 µL sample volume. The validated method was successfully implemented in sample analysis in support of regulated safety studies, with very good results from incurred sample reanalysis. The current LC-MS/MS workflow can be expanded to quantitative analysis of other RLTs in support of preclinical RLT drug development.

Meeting Report on the 2nd Chinese American Society for Mass Spectrometry Conference: Advancing Biological and Pharmaceutical Mass Spectrometry.

The 2nd CASMS conference was held virtually through Gather. Town platform from October 17 to 21, 2022, with a total of 363 registrants including an outstanding and diverse group of scientists at the forefront of their research fields from both academia and industry worldwide, especially in the United States and China. The conference offered a 5-day agenda with an exciting scientific program consisting of two plenary lectures, 14 parallel symposia, and 4 special sessions in which a total of 97 invited speakers presented technological innovations and their applications in proteomics & biological mass spectrometry and metabo-lipidomics & pharmaceutical mass spectrometry. In addition, 18 invited speakers/panelists presented at 3 research-focused and 2 career development workshops. Moreover, 144 posters, 54 lightning talks, 5 sponsored workshops, and 14 exhibitions were presented, from which 20 posters and 8 lightning talks received presentation awards. Furthermore, the conference featured 1 MCP lectureship and 5 young investigator awardees for the first time to highlight outstanding mid-career and early-career rising stars in mass spectrometry from our society. The conference provided a unique scientific platform for young scientists (i.e., graduate students, postdocs and junior faculty/investigators) to present their research, meet with prominent scientists, and learn about career development and job opportunities (http://casms.org).

Non-regulated LC-MS/MS bioanalysis in support of early drug development: a Novartis perspective.

Scientifically qualified LC-MS/MS methods are essential for the determination of small molecule drug candidates and/or their metabolite(s) in support of various non-regulated safety assessment and in vivo absorption, distribution, metabolism and excretion studies in preclinical development. This article outlines an effective method development workflow to fit for this purpose. The workflow features a 'universal' protein precipitation solvent for efficient sample extraction, a mobile phase additive for managing chromatographic resolution and addressing carryover and an internal standard cocktail to select the best analogue internal standard to track the analyte of interest in LC-MS/MS. In addition, good practices are recommended to prevent bioanalytical pitfalls due to instability, non-specific binding and dosing vehicle-induced matrix effect. Proper handling of non-liquid matrix is also discussed.

Matrine can be absorbed and transmitted bidirectionally to defend against aphids (Hemiptera: Aphididae) on wheat and pepper.

BACKGROUND: Although matrine is widely used, its absorption and transport mechanisms in crops remain unexplored. In this study, three methods including foliar application, hydroponics and seed immersion were used to investigate whether matrine molecules could enter into plants through different channels, and to further resolve its transport characteristics. The systemic activity of matrine also was evaluated. RESULT: Matrine was quickly absorbed and transported downwards after the leaves of wheat or peppers were treated, and also accumulated and transmitted upwards by roots. It was not only absorbed by seeds, but also appeared continuously in young roots and leaves in both plants for nearly 20 days. There were some differences in the uptake and conduction of matrine between pepper and wheat: matrine concentrated in pepper upper leaves with less delivered downwards to roots than in wheat, and also transduction of matrine in pepper lower leaves upwards to upper leaves was less than in wheat. Matrine had systemic activity, with LC50 of 361.99 and 904.24 µg·mL-1 against Rhopalosiphum padib on wheat and Myzus persicae (Sulzer) on pepper plants at 48 h, separately. CONCLUSION: Matrine can be absorbed by the roots, seeds and leaves of plants, and transmitted bidirectionally to any organs, presenting satisfactory systemic poisoning activity against aphids. It is of great significance to develop new formulation products of matrine and promote its commercialized value. © 2023 Society of Chemical Industry.

Toxicokinetics in preclinical drug development of small-molecule new chemical entities.

Toxicokinetics (TK) is an integral part of nonclinical (preclinical) safety assessment of small-molecule new chemical entities in drug development. It is employed to describe the systemic exposure of a drug candidate and/or its important metabolite(s) achieved in study animals and elucidate the relationship (proportional, over-proportional, or under-proportional) between systemic exposure and dose administered and the associated differences/similarities between male and female animals along with the possible accumulation/induction. TK data and the derived parameters are employed to propose safe starting doses for clinical use of the new drug candidate through proper extrapolation of findings in study animals to humans. This review has attempted to highlight the health authority expectations on TK assessment in supporting preclinical safety profiling of new chemical entities. A robust TK assessment requires good understanding of absorption, distribution, metabolism, and elimination processes of drug candidate, adequate TK sampling (e.g., controls where relevant), implementation of fit-for-purpose bioanalytical methods (validated or scientifically qualified) along with necessary measures to prevent mis-dosing or ex vivo contamination, and establishment of stability of the drug candidate and/or its metabolite(s) in the intended species matrix to ensure the reliability of bioanalytical and TK data. The latter provides a vital link between animal experiments and human safety.

Enhancement of fluorescence and anti-tumor effect of ZnO QDs by La doping.

ZnO quantum dots (QDs) have received much attention as biomarkers and drug delivery systems in cancer treatment, due to their low cost, ease of preparation, and pH-responsive degradation. However, its applications are limited by the low quantum yield and light absorption. In this work, a lanthanum-doped zinc oxide (La-ZnO) QDs-based drug delivery platform was constructed. The results show that 4% La doping is the most beneficial for improving the fluorescent properties of the ZnO QDs. After loading the drug, the cell activity was 15% at ZnO@DOX and 12% at La-ZnO@DOX. According to in vitro and in vivo experiment results, the La-ZnO QDs show enhancement of the antitumor effect. Dual enhancement of fluorescence and anti-tumor effects make La-ZnO QDs promising as a drug delivery system in cancer treatment.

Harvesting Chlorella vulgaris by electro-flotation with stainless steel cathode and non-sacrificial anode.

As a promising method for efficiently harvesting microalgae, electro-flotation's performance is related to various factors including electrode design and process operating parameters. In this paper, bubble generation behavior on stainless-steel cathodes, with wire diameters of 0.8 mm, 0.2 mm and 0.05 mm, was studied. The results show that the bubble size increased with the increasing diameter of the electrode wire. Over 90 % harvesting efficiency was achieved using non-sacrificial anode. Extracellular polymeric substance is the main reason keeping bubbles from bursting.

Leveraging patient-centric sampling for clinical drug development and decentralized clinical trials: Promise to reality.

Advances in the technologies to enable patient-centric sampling (PCS) have the potential to improve blood sample collection by enabling clinical trial participants to collect samples via self-collection or with the help of a caregiver in their home. Typically, blood samples to assess pharmacokinetics and pharmacodynamics of a drug during clinical development are collected at a clinical site via venous blood draw. In this position paper by the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ), the potential value PCS can bring to patients, to the clinical datasets generated, and to clinical trial sponsors is discussed, along with considerations for program decision making, bioanalytical feasibility, operations, and regulatory implications. With an understanding of the value of PCS and considerations when implementing during clinical drug development, we can bring the promise of PCS closer to reality and enable decentralized clinical trials.

An Improved Math Word Problem (MWP) Model Using Unified Pretrained Language Model (UniLM) for Pretraining.

Natural Language Understanding (NLU) and Natural Language Generation (NLG) are the general methods that support machine understanding of text content. They play a very important role in the text information processing system including recommendation and question and answer systems. There are many researches in the field of NLU such as Bag of words, N-Gram, and neural network language model. These models have achieved a good performance in NLU and NLG tasks. However, since they require lots of training data, it is difficult to obtain rich data in practical applications. Thus, pretraining becomes important. This paper proposes a semisupervised way to deal with math word problem (MWP) tasks using unsupervised pretraining and supervised tuning methods, which are based on the Unified pretrained Language Model (UniLM). The proposed model requires fewer training data than traditional models since it uses model parameters of tasks that have been learned before to initialize the model parameters of new tasks. In this way, old knowledge helps new models successfully perform new tasks from old experiences instead of from scratch. Moreover, in order to help the decoder make accurate predictions, we combine the advantages of AR and AE language models to support one-way, sequence-to-sequence, and two-way predictions. Experiments, carried out on MWP tasks with 20,000+ mathematical questions, show that the improved model outperforms the traditional models with a maximum accuracy of 79.57%. The impact of different experiment parameters is also studied in the paper and we found that a wrong arithmetic order leads to incorrect solution expression generation.

Sensitive LC-MS/MS quantification of unconjugated maytansinoid DM4 and its metabolite S-methyl-DM4 in human plasma.

Aim: To report the development and validation of an LC-MS/MS method for the simultaneous determination of unconjugated payload DM4 and its metabolite S-methyl-DM4 in human plasma. Methodology: A workflow of protein precipitation followed by reduction and solid phase extraction was employed to remove antibody-maytansinoid conjugates from plasma matrix, release DM4 from endogenous conjugates, and generate a clean sample extract for analysis, respectively. Sodium adduct species of both analytes were selected for multiple reaction monitoring to meet the assay sensitivity requirement in liquid chromatography with tandem mass spectrometry. Conclusion: The method was fully validated for a dynamic range of 0.100-50.0 ng/ml for both analytes along with desired stability and acceptable incurred sample reanalysis.

An integrated outsourcing practice of nonclinical LC-MS bioanalysis and toxicokinetics at Novartis small molecule drug development.

With decommissioning of internal regulated bioanalytical (BA) and toxicokinetic (TK) capabilities, Novartis has relied on external service providers (ESPs) for all nonclinical LC-MS BA and majority of the associated TK work since 2017. This paper outlines an integrated outsourcing practice of the Novartis nonclinical LC-MS BA/TK group, which covers the roles and responsibilities of Novartis nonclinical LC-MS BA/TK expert scientific monitors, selection of ESPs for Novartis nonclinical LC-MS BA/TK studies, qualification of BA/TK ESPs, study conduct and completion, ESP oversight and evaluation, issue mitigation, and future perspectives.

The effectiveness of quality control samples in pharmaceutical bioanalysis.

The use of quality control (QC) samples in bioanalysis is well established and consistent with regulatory guidance. However, a systematic evaluation of whether QC samples serve the intended purpose of improving data quality has not been undertaken. The Translational and ADME Sciences Leadership Group (TALG) of the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ) conducted an evaluation to assess whether closer agreement is observed when comparing pharmacokinetic data from two passed runs, than when comparing data from failed and passed (retest) runs. Analysis of data collected across organizations, molecular types and analytical platforms, revealed that bioanalytical methods are very reproducible; and that QC samples improve the overall quality of pharmacokinetic concentration data and justifies their continued use.