PI3K in T Cell Adhesion and Trafficking.

PI3K signalling is required for activation, differentiation, and trafficking of T cells. PI3Kδ, the dominant PI3K isoform in T cells, has been extensively characterised using PI3Kδ mutant mouse models and PI3K inhibitors. Furthermore, characterisation of patients with Activated PI3K Delta Syndrome (APDS) and mouse models with hyperactive PI3Kδ have shed light on how increased PI3Kδ activity affects T cell functions. An important function of PI3Kδ is that it acts downstream of TCR stimulation to activate the major T cell integrin, LFA-1, which controls transendothelial migration of T cells as well as their interaction with antigen-presenting cells. PI3Kδ also suppresses the cell surface expression of CD62L and CCR7 which controls the migration of T cells across high endothelial venules in the lymph nodes and S1PR1 which controls lymph node egress. Therefore, PI3Kδ can control both entry and exit of T cells from lymph nodes as well as the recruitment to and retention of T cells within inflamed tissues. This review will focus on the regulation of adhesion receptors by PI3Kδ and how this contributes to T cell trafficking and localisation. These findings are relevant for our understanding of how PI3Kδ inhibitors may affect T cell redistribution and function

Recombinant snakebite antivenoms: A cost-competitive solution to a neglected tropical disease?

Snakebite envenoming is a major public health burden in tropical parts of the developing world. In sub-Saharan Africa, neglect has led to a scarcity of antivenoms threatening the lives and limbs of snakebite victims. Technological advances within antivenom are warranted, but should be evaluated not only on their possible therapeutic impact, but also on their cost-competitiveness. Recombinant antivenoms based on oligoclonal mixtures of human IgG antibodies produced by CHO cell cultivation may be the key to obtaining better snakebite envenoming therapies. Based on industry data, the cost of treatment for a snakebite envenoming with a recombinant antivenom is estimated to be in the range USD 60-250 for the Final Drug Product. One of the effective antivenoms (SAIMR Snake Polyvalent Antivenom from the South African Vaccine Producers) currently on the market has been reported to have a wholesale price of USD 640 per treatment for an average snakebite. Recombinant antivenoms may therefore in the future be a cost-competitive alternative to existing serum-based antivenoms

Pros and cons of different therapeutic antibody formats for recombinant antivenom development.

Antibody technologies are being increasingly applied in the field of toxinology. Fuelled by the many advances in immunology, synthetic biology, and antibody research, different approaches and antibody formats are being investigated for the ability to neutralize animal toxins. These different molecular formats each have their own therapeutic characteristics. In this review, we provide an overview of the advances made in the development of toxin-targeting antibodies, and discuss the benefits and drawbacks of different antibody formats in relation to their ability to neutralize toxins, pharmacokinetic features, propensity to cause adverse reactions, formulation, and expression for research and development (R&D) purposes and large-scale manufacturing. A research trend seems to be emerging towards the use of human antibody formats as well as camelid heavy-domain antibody fragments due to their compatibility with the human immune system, beneficial therapeutic properties, and the ability to manufacture these molecules cost-effectively

Mind the GAP: RASA2 and RASA3 GTPase-activating proteins as gatekeepers of T cell activation and adhesion.

Following stimulation, the T cell receptor (TCR) and its coreceptors integrate multiple intracellular signals to initiate T cell proliferation, migration, gene expression, and metabolism. Among these signaling molecules are the small GTPases RAS and RAP1, which induce MAPK pathways and cellular adhesion to activate downstream effector functions. Although many studies have helped to elucidate the signaling intermediates that mediate T cell activation, the molecules and pathways that keep naive T cells in check are less understood. Several recent studies provide evidence that RASA2 and RASA3, which are GAP1-family GTPase-activating proteins (GAPs) that inactivate RAS and RAP1, respectively, are crucial molecules that limit T cell activation and adhesion. In this review we describe recent data on the roles of RASA2 and RASA3 as gatekeepers of T cell activation and migration

Phased Array Radio Navigation System on UAVs: In-flight Calibration

Global Navigation Satellite Systems (GNSS) have been the primary positioning solution for Unmanned Aerial Vehicles (UAVs) due to their worldwide coverage, high precision, and lightweight receivers. However, GNSS is prone to electromagnetic interference and malicious assaults, including jamming or spoofing because of its low signal-to-noise ratio (SNR). Using redundant navigation systems is essential to ensure the continuity and protection of UAV operations. In recent years, the phased array radio system (PARS) has established itself as a local navigation solution. PARS is robust towards malicious assaults because of a much higher SNR than GNSS regarding directed and encrypted transmission. An essential factor of PARS is that the orientation of the radio antenna at a ground station needs to be precisely determined to obtain the correct positioning of UAVs. This paper presents a method for extending a previously proposed calibration algorithm to estimate the ground antenna orientation with an inertial navigation system (INS) aided by redundant positioning sensors (GNSS, PARS, or barometer) using a multiplicative extended Kalman filter (MEKF) so that the calibration can be activated during flights whenever GNSS is available. In other words, the proposed navigation system is essentially an aided-INS that switches between two modes depending on the availability of GNSS: calibration and GNSS aiding mode when GNSS is available (Mode 1) and PARS and barometer aiding mode when GNSS is unavailable (Mode 2). Considering that the navigation system needs to include the effect of Earth's curvature for a long-distance flight, PARS horizontal measurement and the barometer measurement were treated independently, and the navigation equations were propagated in Earth Centred Earth Fixed (ECEF) frame. The independent treatment of barometer measurement, and the propagation in ECEF frame were also beneficial when using multiple ground antennas to have a common reference point and reference frame. The proposed method was validated using data (Inertial Measurement Unit (IMU), GNSS, PARS, Pixhawk autopilot (including barometer) measurements) collected during a field test. In the validation, GNSS was made available at the middle of the flight and the calibration mode was activated for 200s. The proposed navigation system successfully estimated the precise orientation of multiple ground antennas and the navigation solutions were verified using GNSS and Pixhawk autopilot solutions as ground truth.</p

Overview of the three different antibody manufacturing process strategies: In the fed-batch process, nutrients for the CHO cells are supplied for a complete cultivation process followed by harvest and purification of the entire batch by single-batch chromatography.

<p>In the continuous perfusion process, cells are retained while the growth medium containing the antibodies is continuously substituted with fresh medium in a perfusion reactor. The used media undergoes simulated moving bed chromatography (SMBC), where the chromatographic processes are conducted in a continuous process as described in [<a href="http://www.plosntds.org/article/info:doi/10.1371/journal.pntd.0005361#pntd.0005361.ref022" target="_blank">22</a>]. In the hybrid process, cultivation is performed in a fed-batch reactor followed by SMBC instead of single-batch chromatography.</p

Estimation of Cost of Goods Manufactured (COGM) per gram for oligoclonal antibody production at different scales of production for three different manufacturing strategies, Fed-batch, hybrid, and continuous perfusion (all using chromatography as purification method, see Fig 2), based on cost estimates from [25,31].

<p>Estimation of Cost of Goods Manufactured (COGM) per gram for oligoclonal antibody production at different scales of production for three different manufacturing strategies, Fed-batch, hybrid, and continuous perfusion (all using chromatography as purification method, see <a href="http://www.plosntds.org/article/info:doi/10.1371/journal.pntd.0005361#pntd.0005361.g002" target="_blank">Fig 2</a>), based on cost estimates from [<a href="http://www.plosntds.org/article/info:doi/10.1371/journal.pntd.0005361#pntd.0005361.ref025" target="_blank">25</a>,<a href="http://www.plosntds.org/article/info:doi/10.1371/journal.pntd.0005361#pntd.0005361.ref031" target="_blank">31</a>].</p