Does Apriority Involve Necessity?

Much has been discussed concerning apriority and its relation to the concept of necessity. Many philosophers have conventionally supposed that a proposition is known a priori only if it is necessarily true. According to Kant, for instance, the first philosopher who systematically discussed apriority, “necessity” is one of the criteriaof a priori knowledge. Kant (1958) maintains that all a priori knowledge is necessarily true. Thus, from this conventional thought, many philosophers claim that apriority involves necessity, and rejecting the concept of necessity unavoidably affects the status of apriority. That is, if all a priori propositions need to be necessarily true, and we can prove that there is no necessarily true proposition, we are forced to conclude that there are no a priori propositions. However, this paper aims to propose that apriority does not involve necessity since all a priori propositions need not be necessarily true. The paper has been separated into three parts. Firstly, I will discussthe problem of necessity and its effect on the status of apriority. Secondly, I will argue that apriority does not involve necessity by considering the two following questions: (A) is there a necessary a posteriori proposition? And (B) is there a contingent a prioriproposition? Thirdly, I will scrutinize the possible objections and try to defend my argument which will involve some further considerations about a priori justification

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

Humanized-Single Domain Antibodies (VH/V<sub>H</sub>H) that Bound Specifically to<em> Naja kaouthia</em> Phospholipase A2 and Neutralized the Enzymatic Activity

<em>Naja kaouthia</em> (monocled cobra) venom contains many isoforms of secreted phospholipase A2 (sPLA<sub>2</sub>). The PLA<sub>2</sub> exerts several pharmacologic and toxic effects in the snake bitten subject, dependent or independent on the enzymatic activity. <em>N. kaouthia</em> venom appeared in two protein profiles, P3 and P5, after fractionating the venom by ion exchange column chromatography. In this study, phage clones displaying humanized-camel single domain antibodies (VH/V<sub>H</sub>H) that bound specifically to the P3 and P5 were selected from a humanized-camel VH/V<sub>H</sub>H phage display library. Two phagemid transfected <em>E. coli</em> clones (P3-1 and P3-3) produced humanized-V<sub>H</sub>H, while another clone (P3-7) produced humanized-VH. At the optimal venom:antibody ratio, the VH/V<sub>H</sub>H purified from the <em>E. coli</em> homogenates neutralized PLA<sub>2</sub> enzyme activity comparable to the horse immune serum against the <em>N. kaouthia</em> holo-venom. Homology modeling and molecular docking revealed that the VH/V<sub>H</sub>H covered the areas around the PLA<sub>2</sub> catalytic groove and inserted their Complementarity Determining Regions (CDRs) into the enzymatic cleft. It is envisaged that the VH/V<sub>H</sub>H would ameliorate/abrogate the principal toxicity of the venom PLA<sub>2</sub> (membrane phospholipid catabolism leading to cellular and subcellular membrane damage which consequently causes hemolysis, hemorrhage, and dermo-/myo-necrosis), if they were used for passive immunotherapy of the cobra bitten victim. The speculation needs further investigations

Pitfalls to avoid when using phage display for snake toxins

Antivenoms against bites and stings from snakes, spiders, and scorpions are associated with immunological side effects and high cost of production, since these therapies are still derived from the serum of hyper-immunized production animals. Biotechnological innovations within envenoming therapies are thus warranted, and phage display technology may be a promising avenue for bringing antivenoms into the modern era of biologics. Although phage display technology represents a robust and high-throughput approach for the discovery of antibody-based antitoxins, several pitfalls may present themselves when animal toxins are used as targets for phage display selection. Here, we report selected critical challenges from our own phage display experiments associated with biotinylation of antigens, clone picking, and the presence of amber codons within antibody fragment structures in some phage display libraries. These challenges may be detrimental to the outcome of phage display experiments, and we aim to help other researchers avoiding these pitfalls by presenting their solutions.UCR::Vicerrectoría de Investigación::Unidades de Investigación::Ciencias de la Salud::Instituto Clodomiro Picado (ICP

Snake venomics of monocled cobra (Naja kaouthia) and investigation of human IgG response against venom toxins

The venom proteome of the monocled cobra, Naja kaouthia, from Thailand, was characterized by RPHPLC, SDS-PAGE, and MALDI-TOF-TOF analyses, yielding 38 different proteins that were either identified or assigned to families. Estimation of relative protein abundances revealed that venom is dominated by three-finger toxins (77.5%; including 24.3% cytotoxins and 53.2% neurotoxins) and phospholipases A2 (13.5%). It also contains lower proportions of components belonging to nerve growth factor, ohanin/ vespryn, cysteine-rich secretory protein, C-type lectin/lectin-like, nucleotidase, phosphodiesterase, metalloproteinase, L-amino acid oxidase, cobra venom factor, and cytidyltransferase protein families. Small amounts of three nucleosides were also evidenced: adenosine, guanosine, and inosine. The most relevant lethal components, categorized by means of a ‘toxicity score’, were a-neurotoxins, followed by cytotoxins/cardiotoxins. IgGs isolated from a person who had repeatedly self-immunized with a variety of snake venoms were immunoprofiled by ELISA against all venom fractions. Stronger responses against larger toxins, but lower against the most critical a-neurotoxins were obtained. As expected, no neutralization potential against N. kaouthia venom was therefore detected. Combined, our results display a high level of venom complexity, unveil the most relevant toxins to be neutralized, and provide prospects of discovering human IgGs with toxin neutralizing abilities through use of phage display screening.UCR::Vicerrectoría de Investigación::Unidades de Investigación::Ciencias de la Salud::Instituto Clodomiro Picado (ICP