Ancient harbour infrastructure in the Levant: tracking the birth and rise of new forms of anthropogenic pressure

Beirut, Sidon and Tyre were major centres of maritime trade from the Bronze Age onwards. This economic prosperity generated increased pressures on the local environment, through urbanization and harbour development. Until now, however, the impact of expanding seaport infrastructure has largely been neglected and there is a paucity of data concerning the environmental stresses caused by these new forms of anthropogenic impacts. Sediment archives from Beirut, Sidon and Tyre are key to understanding human impacts in harbour areas because: (i) they lie at the heart of ancient trade networks; (ii) they encompass the emergence of early maritime infrastructure; and (iii) they enable human alterations of coastal areas to be characterized over long timescales. Here we report multivariate analyses of litho- and biostratigraphic data to probe human stressors in the context of their evolving seaport technologies. The statistical outcomes show a notable break between natural and artificial sedimentation that began during the Iron Age. Three anchorage phases can be distinguished: (i) Bronze Age proto-harbours that correspond to natural anchorages, with minor human impacts; (ii) semi-artificial Iron Age harbours, with stratigraphic evidence for artificial reinforcement of the natural endowments; and (iii) heavy human impacts leading to completely artificial Roman and Byzantine harbours

Aggregation of antibody drug conjugates at room temperature: SAXS and light scattering evidence for colloidal instability of a specific subpopulation

Coupling an hydrophobic drug onto monoclonal antibodies via Lysine residues is a common route to prepare antibody-drug conjugates (ADC), a promising class of biotherapeutics. But a few chemical modifications on protein surface often increases aggregation propensity, without clear understanding of the aggregation mechanisms at stake (loss of colloidal stability, self- assemblies, denaturation...), and the statistical nature of conjugation introduces polydispersity in the ADC population, which raises questions on whether the whole ADC population becomes unstable. To characterize the average interactions between ADC, we monitored small angle X-ray scattering in solutions of monoclonal IgG1 human antibody drug conjugate, with average degree of conjugation of 0, 2, or 3 drug molecules per protein. To characterize stability, we studied kinetics of aggregation at room temperature. Intrinsic Fuchs stability ratio of the ADC was estimated from the variation over time of scattered light intensity and hydrodynamic radius, in buffers of varying pH, and at diverse sucrose (0% or 10%) and NaCl (0 or 100 mM) concentrations. We show that stable ADC stock solutions became unstable upon pH shift, well below the pH of maximum average attraction between IgGs. Data indicates that aggregation can be ascribed to a fraction of ADC population usually representing less than 30 mol% of the sample. In contrast to the case of (monodisperse) monoclonal antibodies, our results suggest that a poor correlation between stability and average interaction parameters should be expected as a corollary of dispersity of ADC conjugation. In practice, the most unstable fraction of the ADC population can be removed by filtrations, which affects remarkably the apparent stability of the samples. Finally, the lack of correlation between the kinetic stability and variations of the average inter-ADC interactions is tentatively attributed to the uneven nature of charge distributions and the presence of patches on the drug-modified antibodies.This work was supported by the French National Research Agency (program Blanc International, grant ANR 2010-INT 1501, and program Investissement d’Avenir ANR-11- LABX-0011-01, and by SANOFI research grant to BFP. Authors are grateful to Javier Perez and Aurélien Thureau for their help and advice in SAXS measurements at SOLEIL. We thank Sophie Norvez from MMC laboratory in ESPCI for her help with circular dichroism.This is the author accepted manuscript. The final version is available from the American Chemical Society via http://dx.doi.org/10.1021/acs.langmuir.6b0065

Aggregation of Antibody Drug Conjugates at Room Temperature: SAXS and Light Scattering Evidence for Colloidal Instability of a Specific Subpopulation

Coupling a hydrophobic drug onto monoclonal antibodies via lysine residues is a common route to prepare antibody–drug conjugates (ADC), a promising class of biotherapeutics. But a few chemical modifications on protein surface often increase aggregation propensity, without a clear understanding of the aggregation mechanisms at stake (loss of colloidal stability, self-assemblies, denaturation, etc.), and the statistical nature of conjugation introduces polydispersity in the ADC population, which raises questions on whether the whole ADC population becomes unstable. To characterize the average interactions between ADC, we monitored small-angle X-ray scattering in solutions of monoclonal IgG1 human antibody drug conjugate, with average degree of conjugation of 0, 2, or 3 drug molecules per protein. To characterize stability, we studied the kinetics of aggregation at room temperature. The intrinsic Fuchs stability ratio of the ADC was estimated from the variation over time of scattered light intensity and hydrodynamic radius, in buffers of varying pH, and at diverse sucrose (0% or 10%) and NaCl (0 or 100 mM) concentrations. We show that stable ADC stock solutions became unstable upon pH shift, well below the pH of maximum average attraction between IgGs. Data indicate that aggregation can be ascribed to a fraction of ADC population usually representing less than 30 mol % of the sample. In contrast to the case of (monodisperse) monoclonal antibodies, our results suggest that a poor correlation between stability and average interaction parameters should be expected as a corollary of dispersity of ADC conjugation. In practice, the most unstable fraction of the ADC population can be removed by filtration, which affects remarkably the apparent stability of the samples. Finally, the lack of correlation between the kinetic stability and variations of the average inter-ADC interactions is tentatively attributed to the uneven nature of charge distributions and the presence of patches on the drug-modified antibodies

The weak password problem: chaos, criticality, and encrypted p-CAPTCHAs

Vulnerabilities related to weak passwords are a pressing global economic and security issue. We report a novel, simple, and effective approach to address the weak password problem. Building upon chaotic dynamics, criticality at phase transitions, CAPTCHA recognition, and computational round-off errors we design an algorithm that strengthens security of passwords. The core idea of our method is to split a long and secure password into two components. The first component is memorized by the user. The second component is transformed into a CAPTCHA image and then protected using evolution of a two-dimensional dynamical system close to a phase transition, in such a way that standard brute-force attacks become ineffective. We expect our approach to have wide applications for authentication and encryption technologies.Comment: 5 pages, 6 figer

A “Soft” Approach to Analysing Mobile Financial Services Sociotechnical Systems

Advances in mobile computing have presented a huge opportunity to provide Mobile Financial Services (MFS) to half of the world’s population who currently do not have access to financial services. However, cybersecurity concerns in the mobile computing ecosystem have slowed down the adoption of MFS. The adoption of MFS is further hampered by the lack of a clear understanding of the interaction between the complex infrastructures and human factors that exist in the ecosystem for Mobile Financial Services Socio-Technical Systems (MFSSTS). This paper presents the work in progress of investigating the problem of MFSSTS. It discusses the preliminary results and understanding obtained from using Human Factor approaches to build and analyse the model for MFSSTS

Paediatric patient safety and the need for aviation black box thinking to learn from and prevent medication errors

Since the publication of To Err Is Human: Building a Safer Health System in 1999, there has been much research conducted into the epidemiology, nature and causes of medication errors in children, from prescribing and supply to administration. It is reassuring to see growing evidence of improving medication safety in children; however, based on media reports, it can be seen that serious and fatal medication errors still occur. This critical opinion article examines the problem of medication errors in children and provides recommendations for research, training of healthcare professionals and a culture shift towards dealing with medication errors. There are three factors that we need to consider to unravel what is missing and why fatal medication errors still occur. (1) Who is involved and affected by the medication error? (2) What factors hinder staff and organisations from learning from mistakes? Does the fear of litigation and criminal charges deter healthcare professionals from voluntarily reporting medication errors? (3) What are the educational needs required to prevent medication errors? It is important to educate future healthcare professionals about medication errors and human factors to prevent these from happening. Further research is required to apply aviation’s ‘black box’ principles in healthcare to record and learn from near misses and errors to prevent future events. There is an urgent need for the black box investigations to be published and made public for the benefit of other organisations that may have similar potential risks for adverse events. International sharing of investigations and learning is also needed