Charge Berezinskii-Kosterlitz-Thouless transition in superconducting NbTiN films

A half-century after the discovery of the superconductor-insulator transition (SIT), one of the fundamental predictions of the theory, the charge Berezinskii-Kosterlitz-Thouless (BKT) transition that is expected to occur at the insulating side of the SIT, has remained unobserved. The charge BKT transition is a phenomenon dual to the vortex BKT transition, which is at the heart of the very existence of two-dimensional superconductivity as a zero-resistance state appearing at finite temperatures. The dual picture points to the possibility of the existence of a superinsulating state endowed with zero conductance at finite temperature. Here, we report the observation of the charge BKT transition on the insulating side of the SIT, identified by the critical behavior of the resistance. We find that the critical temperature of the charge BKT transition depends on the magnetic field exhibiting first the fast growth and then passing through the maximum at fields much less than the upper critical field. Finally, we ascertain the effects of the finite electrostatic screening length and its divergence at the magnetic field-tuned approach to the superconductor-insulator transition.Comment: 9 pages, 6 figure

Global guidance on environmental life cycle impact assessment indicators: Progress and case study

International audiencePurpose: The life cycle impact assessment (LCIA) guidance flagship project of the United Nations Environment Programme (UNEP)/Society of Environmental Toxicology and Chemistry (SETAC) Life Cycle Initiative aims at providing global guidance and building scientific consensus on environmental LCIA indicators. This paper presents the progress made since 2013, preliminary results obtained for each impact category and the description of a rice life cycle assessment (LCA) case study designed to test and compare LCIA indicators. Methods: The effort has been focused in a first stage on impacts of global warming, fine particulate matter emissions, water use and land use, plus cross-cutting issues and LCA-based footprints. The paper reports the process and progress and specific results obtained in the different task forces (TFs). Additionally, a rice LCA case study common to all TF has been developed. Three distinctly different scenarios of producing and cooking rice have been defined and underlined with life cycle inventory data. These LCAs help testing impact category indicators which are being developed and/or selected in the harmonisation process. The rice LCA case study further helps to ensure the practicality of the finally recommended impact category indicators. Results and discussion: The global warming TF concludes that analysts should explore the sensitivity of LCA results to metrics other than GWP. The particulate matter TF attained initial guidance of how to include health effects from PM2.5 exposures consistently into LCIA. The biodiversity impacts of land use TF suggests to consider complementary metrics besides species richness for assessing biodiversity loss. The water use TF is evaluating two stress-based metrics, AWaRe and an alternative indicator by a stakeholder consultation. The cross-cutting issues TF agreed upon maintaining disability-adjusted life years (DALY) as endpoint unit for the safeguard subject 'human health'. The footprint TF defined main attributes that should characterise all footprint indicators. 'Rice cultivation' and 'cooking' stages of the rice LCA case study contribute most to the environmental impacts assessed. Conclusions: The results of the TF will be documented in white papers and some published in scientific journals. These white papers represent the input for the Pellston workshop', taking place in Valencia, Spain, from 24 to 29 January 2016, where best practice, harmonised LCIA indicators and an update on the general LCIA framework will be discussed and agreed on. With the diversity in results and the multi-tier supply chains, the rice LCA case study is well suited to test candidate recommended indicators and to ensure their applicability in common LCA case studies

ADME Considerations and Bioanalytical Strategies for Pharmacokinetic Assessments of Antibody-Drug Conjugates

Antibody-drug conjugates (ADCs) are a unique class of biotherapeutics of inherent heterogeneity and correspondingly complex absorption, distribution, metabolism, and excretion (ADME) properties. Herein, we consider the contribution of various components of ADCs such as various classes of warheads, linkers, and conjugation strategies on ADME of ADCs. Understanding the metabolism and disposition of ADCs and interpreting exposure-efficacy and exposure-safety relationships of ADCs in the context of their various catabolites is critical for design and subsequent development of a clinically successful ADCs. Sophisticated bioanalytical assays are required for the assessments of intact ADC, total antibody, released warhead and relevant metabolites. Both ligand-binding assays (LBA) and hybrid LBA-liquid chromatography coupled with tandem mass spectrometry (LBA-LC-MS/MS) methods have been employed to assess pharmacokinetics (PK) of ADCs. Future advances in bioanalytical techniques will need to address the rising complexity of this biotherapeutic modality as more innovative conjugation strategies, antibody scaffolds and novel classes of warheads are employed for the next generation of ADCs. This review reflects our considerations on ADME of ADCs and provides a perspective on the current bioanalytical strategies for pharmacokinetic assessments of ADCs

Differences in levels of phosphatidylinositols in healthy and stable Coronary Artery Disease subjects revealed by HILIC-MRM method with SERRF normalization.

Quantification of endogenous biomarkers in clinical studies requires careful evaluation of a number of assay performance parameters. Comparisons of absolute values from several clinical studies can enable retrospective analyses further elucidating the biology of a given biomarker across various study populations. We characterized the performance of a highly multiplex bioanalytical method for quantification of phosphatidylinositols (PI). Hydrophilic interaction chromatography (HILIC) and multiple reaction monitoring (MRM) were employed for targeted multiplex quantification. Odd-chain PI species that are not normally present in human plasma were utilized as surrogate analytes (SA) to assess various assay performance parameters and establish a definitive dynamic linear range for PI lipids. To correct for batch effects, Systematic Error Removal using Random Forest (SERRF) normalization algorithm was employed and used to bridge raw values between two clinical studies, enabling quantitative comparison of their absolute values. A high throughput method was developed, qualified, transferred to an automation platform and applied to sample testing in two clinical trials in healthy volunteers (NCT03001297) and stable Coronary Artery Disease (CAD, NCT03351738) subjects. The method demonstrated acceptable precision and accuracy (±30%) over linear range of 1-1000 nM for SA and 8-fold dilutional linearity for endogenous PI. We determined that mean-adjusted average QC performed best for normalization using SERRF. The comparison of two studies revealed that healthy subject levels of PI are consistently higher across PI species compared to CAD subjects identifying a potential lipid biomarker to be explored in future studies

Multiplex LC-MS/MS Assays for Clinical Bioanalysis of MEDI4276, an Antibody-Drug Conjugate of Tubulysin Analogue Attached via Cleavable Linker to a Biparatopic Humanized Antibody against HER-2

Bioanalysis of complex biotherapeutics, such as antibody-drug conjugates (ADCs), is challenging and requires multiple assays to describe their pharmacokinetic (PK) profiles. To enable exposure-safety and exposure-efficacy analyses, as well as to understand the metabolism of ADC therapeutics, three bioanalytical methods are typically employed: Total Antibody, Antibody Conjugated Toxin or Total ADC and Unconjugated Toxin. MEDI4276 is an ADC comprised of biparatopic humanized antibody attached via a protease-cleavable peptide-based maleimidocaproyl linker to a tubulysin toxin (AZ13599185) with an approximate average drug-antibody ratio of 4. The conjugated payload of MEDI4276 can undergo ester hydrolysis to produce the conjugated payload AZ13687308, leading to the formation of MEDI1498 (de-acetylated MEDI4276). In this report, we describe the development, validation and application of three novel multiplex bioanalytical methods. The first ligand-binding liquid chromatography coupled with tandem mass spectrometry (LBA-LC-MS/MS) method was developed and validated for simultaneous measurement of total antibody and total ADC (antibody-conjugated AZ13599185) from MEDI4276. The second LBA-LC-MS/MS assay quantified total ADC (antibody-conjugated AZ13687308) from MEDI1498. The third multiplex LC-MS/MS assay was used for simultaneous quantification of unconjugated AZ13599185 and AZ13687308. Additional stability experiments confirmed that quantification of the released warhead in the presence of high concentrations of MEDI4276 was acceptable. Subsequently, the assays were employed in support of a first-in-human clinical trial (NCT02576548)

Supplementary materials: Comprehensive performance evaluation ofligand binding assay–LC–MS/MS method forco-dosed monoclonal anti-SARS-CoV-2antibodies (AZD7442)

Aims: AZD7442 is a combination SARS-CoV-2 therapy comprising two co-dosed monoclonal antibodies. Materials & methods: The authors validated a hybrid ligand-binding assay–LC–MS/MS method for pharmacokinetic assessment of AZD7442 in human serum with nominal concentration range of each analyte of 0.300–30.0 μg/ml. Results: Validation results met current regulatory acceptance criteria. The validated method supported three clinical trials that spanned more than 17 months and ≥720 analytical runs (∼30,000 samples and ∼3000 incurred sample reanalyses per analyte). The data generated supported multiple health authority interactions, across the globe. AZD7442 (EVUSHELD) was approved in 12 countries for pre-exposure prophylaxis of COVID-19. Conclusion: The results reported here demonstrate the robust, high-throughput capability of the hybrid ligand binding assay–LC–MS/MS approach being employed to support-next generation versions of EVUSHELD, AZD3152.</p

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