High sensitivity detection of nanoparticles permeation through polymer membranes: A physico-chemical and nuclear imaging measurement approach

Diffusion cells are devices made of donor and acceptor compartments (DC and AC), separated by a membrane. They are widely used in pharmaceutical, cosmetic, toxicology, and protective equipment tests (e.g., gloves) to measure the kinetics of permeants (molecules and nanoparticles) across biological membranes as the skin. However, rarely is the concentration of permeants in the AC measured in continuous or in real-time, and this limitation leads to significant discrepancies in the calculations of kinetic parameters that define the permeation mechanisms. In this study, a diffusion cell compatible with positron emission tomography was used to measure the permeation kinetics of nanoparticles across glove membranes. The technology allows for the measurement of nanoparticle concentration in real-time in the two compartments (DC and AC) and at a detection sensitivity several orders of magnitude higher compared with conventional spectroscopies, thus allowing a much more precise extraction of kinetic parameters. Ultra-small (<10 nm) gold nanoparticles were used as a model nanoparticle contaminant. They were radiolabeled, and their diffusion kinetics was measured in continuous through latex and nitrile polymer membranes. Permeation profiles were recorded at sub-nanomolar sensitivity and in real-time, thus allowing the high precision extraction of kinetic permeation parameters. The technology, methodology, and data extraction process developed in this work could be applied to measure in real-time the kinetics of diffusion of a whole range of potentially toxic molecules and nanoparticles across polymer membranes, including glove membranes

Terrestrial spatial ecology of female New Zealand sea lions: Study at Sandy Bay, Auckland Islands, and implication for the management of the recolonisation

The New Zealand sea lion, Phocarctos hookeri, is endemic to New Zealand and has only three breeding colonies, all situated in the sub-Antarctic islands. This reduced breeding distribution is the result of human extirpation from most of its pristine range, which included the New Zealand mainland. In 1993, a female bred for the first time on mainland New Zealand, indicating the possible start of the recolonisation. The recolonisation of an urbanised coastline will create interactions between humans, infrastructures and sea lions. No study had however looked at how the New Zealand sea lion uses its terrestrial environment. This study thus aimed to characterise, in space and time, the terrestrial spatial ecology of the female New Zealand sea lions at a breeding colony. Intensive fieldwork at the Sandy Bay breeding colony, Enderby Island, in the Auckland Islands, during two breeding seasons (between December 2001 and March 2003), produced a large dataset of daily Global Positioning System (GPS) locations of branded females onshore (4252 locations) within the study area (0.7 km²). A habitat type map and a Digital Terrain Model (DTM) of the study area were produced. The analyses were conducted in ArcGIS at three scales: individual, population and habitat. A two-phase pattern, including a harem phase (aggregation of females, area used 0.550 km²), was revealed and characterised using Nearest Neighbour Indices. A dispersion model of an average female was produced based on cumulative Minimum Convex Polygons (MCP) and pup mortality was found to be affected by females’ movements on pupping day. The female population was found to move and shift areas used throughout the dispersion phase while the gregariousness of females was considerably modified between the harem phase and the end of the dispersion phase (80 versus 0.3 females per 100 m²). Temporal analyses of habitat use demonstrated a radical change in habitat preferences between the two phases and a gradual change during the dispersion phase. At the end of the season, females preferred sites in forest and at more than 1.1 km from shore. Male aggressiveness and disturbance, habitat properties and parasite infections are thought to be some of the main factors that drive the terrestrial ecology of the females P. hookeri. In conclusion, the presence and spatial extent of a female population at Sandy Bay, unusual for a pinniped species, was found to be predictable and thought to be species- specific rather than location-specific. The results of this study can thus be used as a basis for the management of the recolonisation. Human infrastructure and disturbance are likely to interfere with the establishment of new breeding colonies and the ecology of female New Zealand sea lions on mainland New Zealand. Some recommendations based on these results are immediate public awareness and education programs, the monitoring of the new population using a GIS database and the identification, protection against human disturbance and rehabilitation of suitable sites for the establishment of a new breeding colony on the mainland

Terrestrial spatial ecology of female New Zealand sea lions: Study at Sandy Bay, Auckland Islands, and implication for the management of the recolonisation

The New Zealand sea lion, Phocarctos hookeri, is endemic to New Zealand and has only three breeding colonies, all situated in the sub-Antarctic islands. This reduced breeding distribution is the result of human extirpation from most of its pristine range, which included the New Zealand mainland. In 1993, a female bred for the first time on mainland New Zealand, indicating the possible start of the recolonisation. The recolonisation of an urbanised coastline will create interactions between humans, infrastructures and sea lions. No study had however looked at how the New Zealand sea lion uses its terrestrial environment. This study thus aimed to characterise, in space and time, the terrestrial spatial ecology of the female New Zealand sea lions at a breeding colony. Intensive fieldwork at the Sandy Bay breeding colony, Enderby Island, in the Auckland Islands, during two breeding seasons (between December 2001 and March 2003), produced a large dataset of daily Global Positioning System (GPS) locations of branded females onshore (4252 locations) within the study area (0.7 km²). A habitat type map and a Digital Terrain Model (DTM) of the study area were produced. The analyses were conducted in ArcGIS at three scales: individual, population and habitat. A two-phase pattern, including a harem phase (aggregation of females, area used 0.550 km²), was revealed and characterised using Nearest Neighbour Indices. A dispersion model of an average female was produced based on cumulative Minimum Convex Polygons (MCP) and pup mortality was found to be affected by females’ movements on pupping day. The female population was found to move and shift areas used throughout the dispersion phase while the gregariousness of females was considerably modified between the harem phase and the end of the dispersion phase (80 versus 0.3 females per 100 m²). Temporal analyses of habitat use demonstrated a radical change in habitat preferences between the two phases and a gradual change during the dispersion phase. At the end of the season, females preferred sites in forest and at more than 1.1 km from shore. Male aggressiveness and disturbance, habitat properties and parasite infections are thought to be some of the main factors that drive the terrestrial ecology of the females P. hookeri. In conclusion, the presence and spatial extent of a female population at Sandy Bay, unusual for a pinniped species, was found to be predictable and thought to be species- specific rather than location-specific. The results of this study can thus be used as a basis for the management of the recolonisation. Human infrastructure and disturbance are likely to interfere with the establishment of new breeding colonies and the ecology of female New Zealand sea lions on mainland New Zealand. Some recommendations based on these results are immediate public awareness and education programs, the monitoring of the new population using a GIS database and the identification, protection against human disturbance and rehabilitation of suitable sites for the establishment of a new breeding colony on the mainland

Foraging behaviour of juvenile female New Zealand sea lions (Phocarctos hookeri) in contrasting environments

Foragers can show adaptive responses to changes within their environment through morphological and behavioural plasticity. We investigated the plasticity in body size, at sea movements and diving behaviour of juvenile female New Zealand (NZ) sea lions (Phocarctos hookeri) in two contrasting environments. The NZ sea lion is one of the rarest pinnipeds in the world. Most of the species is based at the subantarctic Auckland Islands (AI; considered to be marginal foraging habitat), with a recolonizing population on the Otago Peninsula, NZ mainland (considered to be more optimal habitat). We investigated how juvenile NZ sea lions adjust their foraging behaviour in contrasting environments by deploying satellite-linked platform transmitting terminals (PTTs) and time-depth recorders (TDRs) on 2–3 year-old females at AI (2007–2010) and Otago (2009–2010). Juvenile female NZ sea lions exhibited plasticity in body size and behaviour. Otago juveniles were significantly heavier than AI juveniles. Linear mixed effects models showed that study site had the most important effect on foraging behaviour, while mass and age had little influence. AI juveniles spent more time at sea, foraged over larger areas, and dove deeper and longer than Otago juveniles. It is difficult to attribute a specific cause to the observed contrasts in foraging behaviour because these differences may be driven by disparities in habitat/prey characteristics, conspecific density levels or interseasonal variation. Nevertheless, the smaller size and increased foraging effort of AI juveniles, combined with the lower productivity in this region, support the hypothesis that AI are less optimal habitat than Otago. It is more difficult for juveniles to forage in suboptimal habitats given their restricted foraging ability and lower tolerance for food limitation compared to adults. Thus, effective management measures should consider the impacts of low resource environments, along with changes that can alter food availability such as potential resource competition with fisheries

The CD33xCD123xCD70 Multispecific CD3-Engaging DARPin MP0533 Induces Selective T Cell-Mediated Killing of AML Leukemic Stem Cells.

The prognosis of patients with acute myeloid leukemia (AML) is limited, especially for elderly or unfit patients not eligible for hematopoietic stem cell (HSC) transplantation. The disease is driven by leukemic stem cells (LSCs), which are characterized by clonal heterogeneity and resistance to conventional therapy. These cells are therefore believed to be a major cause of progression and relapse. We designed MP0533, a multispecific CD3-engaging DARPin (designed ankyrin repeat protein) that can simultaneously bind to three antigens on AML cells (CD33, CD123, and CD70), aiming to enable avidity-driven T cell-mediated killing of AML cells co-expressing at least two of the antigens. In vitro, MP0533 induced selective T cell-mediated killing of AML cell lines, as well as patient-derived AML blasts and LSCs, expressing two or more target antigens, while sparing healthy HSCs, blood, and endothelial cells. The higher selectivity also resulted in markedly lower levels of cytokine release in normal human blood compared to single antigen-targeting T-cell engagers. In xenograft AML mouse models, MP0533 induced tumor-localized T-cell activation and cytokine release, leading to complete eradication of the tumors while having no systemic adverse effects. These studies show that the multispecific-targeting strategy used with MP0533 holds promise for improved selectivity towards LSCs and efficacy against clonal heterogeneity, potentially bringing a new therapeutic option to this group of patients with high unmet need. MP0533 is currently being evaluated in a dose-escalation phase 1 study in patients with relapsed or refractory AML (NCT05673057)