The relationship between antibody redox structure and affinity in rainbow trout

Teleost immunoglobulin M (IgM), an 800 kDa tetramer, possesses considerable structural diversity due to the non-uniform disulfide polymerization of its halfmeric or monomeric subunits. However, to date, no plausible functional role for this diversity has been demonstrated or proposed. This research was, therefore, designed to investigate the possible functional role(s) for this diversity using the trout model. The possible relationship between this structural diversity and affinity was specifically addressed. The relationship between high levels of disulfide polymerization and high affinity was demonstrated by selective immunoadsorption and analysis of antibodies isolated during the process of affinity maturation. A pivotal determinative role of antigen/BCR affinity in conferring graded levels of disulfide bonding was demonstrated by the induction of high and mixed affinity antibodies from a single lymphocyte source in vitro. Additionally, transfer of immunopurified antibodies and labeled non-immune immunoglobulins revealed a direct effect of polymerization on antibody half-life, with selective removal of less polymerized Igs and/or retention of more fully polymerized Igs. Thus, this differential effect on half-life also results in an increase of average affinity, accentuating the process of affinity maturation. The converse, modulation of affinity by disulfide variation; however, could not be demonstrated

Evaluation of pharmacokinetics and toxicology of biosimilar APZ001 antibody in Macaca cynomolgus

Purpose: To compare the pharmacokinetics of APZ001 antibody with those of cetuximab (Erbitux®) and to evaluate the toxicology of the former.Methods: To evaluate cetuximab’s biosimilar APZ001, Crl:CD1(ICR) (CD-1) mice and Macaca fascicularis (cynomolgus monkey) were chosen for the studies on acute toxicity, chronic toxicity, pharmacokinetics in chronic toxicity and immunogenicity toxicity. The study also compared the pharmacokinetic parameters of APZ001 with those of cetuximab upon single and multiple drug administrations in cynomolgus monkeys.Results: Pharmacokinetic parameters including maximum concentration (Cmax) and time to attain maximum drug concentration (Tmax), clearance rate and apparent volume of distribution of APZ001 were compared with those of cetuximab in both single and multiple administration studies. Difference of pharmacokinetics from weekly administration of APZ001 and cetuximab in cynomolgus monkeys was insignificant (p > 0.05), with relative bioavailability of 116.9 %. Both APZ001-treated and cetuximabtreated CD-1 mice showed the same level of food intake and body weight. Hematological and serological data were similar from APZ001 antibody and cetuximab treatments, so were the acute and chronic toxicity. Weekly transfusion of APZ001 did not alter its pharmacokinetic parameters. The administered drug was hardly detected in the serum in the 31st and 37th week of recovery; no accumulation of drug was observed upon withdrawal.Conclusion: APZ001 has extremely similar characteristics as cetuximab in terms of pharmacokinetics and toxicity.Keywords: Cetuximab, Pharmacokinetics, Acute toxicity, Chronic toxicity, Immunogenicity, Biosimila

Reinforcement Learning for Robot Navigation with Adaptive Forward Simulation Time (AFST) in a Semi-Markov Model

Deep reinforcement learning (DRL) algorithms have proven effective in robot navigation, especially in unknown environments, by directly mapping perception inputs into robot control commands. However, most existing methods ignore the local minimum problem in navigation and thereby cannot handle complex unknown environments. In this paper, we propose the first DRL-based navigation method modeled by a semi-Markov decision process (SMDP) with continuous action space, named Adaptive Forward Simulation Time (AFST), to overcome this problem. Specifically, we reduce the dimensions of the action space and improve the distributed proximal policy optimization (DPPO) algorithm for the specified SMDP problem by modifying its GAE to better estimate the policy gradient in SMDPs. Experiments in various unknown environments demonstrate the effectiveness of AFST

Mucin Production and Mucous Cell Metaplasia in Otitis Media

Otitis media (OM) with mucoid effusion, characterized by mucous cell metaplasia/hyperplasia in the middle ear cleft and thick fluid accumulation in the middle ear cavity, is a subtype of OM which frequently leads to chronic OM in young children. Multiple factors are involved in the developmental process of OM with mucoid effusion, especially disorders of mucin production resulting from middle ear bacterial infection and Eustachian tube dysfunction. In this review, we will focus on several aspects of this disorder by analyzing the cellular and molecular events such as mucin production and mucous cell differentiation in the middle ear mucosa with OM. In addition, infectious agents, mucin production triggers, and relevant signaling pathways will be discussed

Induction of a torpor-like hypothermic and hypometabolic state in rodents by ultrasound

Torpor is an energy-conserving state in which animals dramatically decrease their metabolic rate and body temperature to survive harsh environmental conditions. Here, we report the noninvasive, precise and safe induction of a torpor-like hypothermic and hypometabolic state in rodents by remote transcranial ultrasound stimulation at the hypothalamus preoptic area (POA). We achieve a long-lasting (\u3e24 h) torpor-like state in mice via closed-loop feedback control of ultrasound stimulation with automated detection of body temperature. Ultrasound-induced hypothermia and hypometabolism (UIH) is triggered by activation of POA neurons, involves the dorsomedial hypothalamus as a downstream brain region and subsequent inhibition of thermogenic brown adipose tissue. Single-nucleus RNA-sequencing of POA neurons reveals TRPM2 as an ultrasound-sensitive ion channel, the knockdown of which suppresses UIH. We also demonstrate that UIH is feasible in a non-torpid animal, the rat. Our findings establish UIH as a promising technology for the noninvasive and safe induction of a torpor-like state