Discovery and structure–activity relationships of small molecules that block the human immunoglobulin G–human neonatal Fc receptor (hIgG–hFcRn) protein–protein interaction

The neonatal Fc receptor, FcRn, prolongs the half-life of IgG in the serum and represents a potential therapeutic target for the treatment of autoimmune disease. Small molecules that block the protein–protein interactions of human IgG–human FcRn may lower pathogenic autoantibodies and provide effective treatment. A novel class of quinoxalines has been discovered as antagonists of the IgG:FcRn protein–protein interaction through optimization of a hit derived from a virtual ligand-based screen.     

Use of a radioimmunoassay technique to measure the titer of anti-cow-zona antibodies in marmoset monkeys

A double antibody radioimmunoassay technique is described for the measurement of anti-zona antibodies in the peripheral plasma of marmosets actively immunized against intact cow zonae pellucidae. The method has been shown to be a reliable, repeatable indicator of antibody titer, enabling direct comparison of the response obtained between marmosets. This is the first report of a procedure describing the active immunization of a primate against zona antigens, and the first time a radioimmunoassay technique has been used to monitor profiles of anti-cow zona antibody production following active immunization. The method should prove to be a useful tool in the evaluation of zona antigens as agents for immunocontraception.     

Amino acid sequence surrounding the lipoic acid cofactor of bovine kidney 2-oxoglutarate dehydrogenase complex

The 2-oxoglutarate dehydrogenase complex was succinylated using 2-oxo[5-14C]glutarate in the presence of N-ethylmaleimide to label the lipoic acid cofactor of the transuccinylase (E2) component. Following peptic digestion, 14C-lipoate-containing peptides were purified and subjected to automated Edman degradation and amino acid analysis. The amino acid sequence surrounding the lipoyllysine residue is reported.     

Thermal sensitivity of scope for activity in Pagothenia borchgrevinki, a cryopelagic Antarctic nototheniid fish

The thermal sensitivity of scope for activity was studied in the Antarctic nototheniid fish Pagothenia borchgrevinki. The scope for activity of P. borchgrevinki at 0°C was 189 mg O₂ kg⁻¹ h⁻¹ (factorial scope 6.8) which is similar to that of temperate and tropical species at their environmental temperatures, providing no evidence for metabolic cold adaptation of maximum activity. The scope for activity increased to a maximum value of 266 mg O₂ kg⁻¹ h⁻¹ (factorial scope 8.3) at 3°C and then decreased from 3 to 6°C. The thermal sensitivity of critical swimming speed was also investigated and followed a similar pattern to aerobic scope for activity, suggesting oxygen limitation of aerobic performance. Oxygen consumption rates and ventilation frequencies were monitored for 24 h after the swimming challenge and the recovery of both parameters to resting levels was rapid and independent of temperature.     

Embryonal carcinoma-derived growth factor activates protein kinase C in vivo and in vitro.

We have recently reported that a polypeptide mitogen, the embryonal carcinoma-derived growth factor (ECDGF), induces phosphorylation of the epidermal growth factor (EGF) receptor in intact C3H 10T 1/2 mouse fibroblasts with concomittant loss of high affinity EGF binding sites. This phenomenon appears to be mediated through an activation of protein kinase C. Several groups have described an acidic 80,000 dalton protein substrate of protein kinase C. In this paper, we demonstrate that the addition of ECDGF or the phorbol ester TPA to intact C3H 10T 1/2 cells results in the enhanced phosphorylation of this 80 kd protein in vivo. Furthermore, this response is demonstrable in vitro. Thus the addition of ECDGF, the phorbol ester TPA, protein kinase C or phosphoinositidase C to crude membranes prepared from C3H 10T 1/2 cells resulted in the enhanced phosphorylation of this protein. Data obtained by phosphopeptide mapping of the 80 kd protein show that the ECDGF-induced activation of protein kinase C in our membrane preparations is comparable with that obtained in vivo. The availability of an in vitro system in which this response is preserved should now allow a detailed biochemical analysis of the steps between binding of a mitogen to its receptor and the activation of protein kinase C.     

Pathophysiology of pH and Ca2+ in bloodstream and brain

The highlights of the literature and our work on tetany and hyperventilation are reviewed. Our studies concern the following: (1) the changes of [Ca2+] in circulating plasma caused by respiratory and "metabolic" acidosis and alkalosis; (2) critical plasma [Ca2+] levels associated with signs of tetany and neuromuscular blockade; (3) changes in cerebral [Ca2+]o caused by hypo- and hyper-calcaemia, and the changes in cerebral [Ca2+]o and pHo caused by acute systemic acidosis and alkalosis; and (4) effects of changing [Ca2+]o and pHo levels on synaptic transmission in hippocampal formation. Our main conclusions are (1) changes of plasma [Ca2+] caused by "metabolic" pH changes are greater than those associated with varying CO2 concentration; (2) acute systemic [Ca2+] changes are associated with small cerebral [Ca2+]o changes; (3) the decreases in systemic and cerebral [Ca2+]o caused by hyperventilation are too small to account for the signs and symptoms of hypocapnic tetany; (4) moderate decrease of [Ca2+]o depresses and its increase enhances synaptic transmission in hippocampal formation; and (5) H+ ions in extracellular fluid have a weak depressant effect on neuronal excitability. CO2 is a strong depressant, which is only partly explained by the acidity of its solution. CO2 concentration is a significant factor in controlling cerebral function.     

Humid air increases airway resistance in asthmatic subjects.

Eight persons with asthma were exposed to seven air conditions varying in temperature (37 degrees C to 49 degrees C [98.6 degrees F to 120.2 degrees F]) and water content (44 mg H2O per liter to 79 mg H2Oper liter) . Normocapnic hyperventilation for three minutes at 40% maximal voluntary ventilation was carried out for each condition. A constant-volume body plethysmograph measured the functional residual capacity and specific airway conductance (SGaw), followed by two forced expiratory manuevers. Measurements were taken before and 1, 5, 10, and 20 minutes after each challenge. Air conditions with 100% relative humidity caused a fall in the SGaw that was maximal in 1 minute. Air conditions at 100% relative humidity caused a greater fall in both the forced expiratory volume in 1 second (FEV1) (P<.05) and the SGaw (P<.005) than did conditions of the same temperature but less water content. At 44 degrees C and 100% relative humidity, the mean percent change in FEV1 and SGaw was -2% and -40%, respectively, at 1 minute after challenge. Of the conditions examined, the optimal temperature was 44 degrees C, and we speculate that the optimal water content is less than 44 mg H2O per liter. Inhaled water concentrations exceeding 44 mg H2O per liter should probably not be used in patients with asthma.     

Contraceptive potential of antibodies to the zona pellucida

The notion of a contraceptive vaccine based on gamete-specific surface antigens was first proposed over a decade ago, as the result of in-vitro and in-vivo studies, and in recent years has been the subject of intensive research. In particular, the zona pellucida has attracted much attention as a potential target for immunological intervention in the fertilization process. Such is the rapidly-expanding nature of research into the biochemical and biological characterization of this structure, that a review of the implications for the development of a contraceptive vaccine seems timely.