The effect of isoelectric amino acids on the pH(+) of a phosphate buffer solution - A contribution in support of the "Zwitter Ion" hypothesis

The relative merits of the classical conception and of the Zwitter Ion conception of the dissociation of amphoteric electrolytes are discussed, and the following data are presented which confirm the Zwitter Ion hypothesis of Bjerrum, and which are not in accord with the classical view. 1. Amino acids in the isoelectric form resemble strong electrolytes in that they contribute to the ionic strength of the solution. 2. The dielectric constants of aqueous solutions of amino acids, like those of solutions of strong electrolytes greater than 0.02 normal, are considerably greater than that of pure water. 3. The magnitude of the dissociation constants of substituted acetic acids and of glycine, are more easily accounted for with the Zwitter Ion than with the classical conception

The substrate in peptic synthesis of protein

Experiments are described in which it was observed that the yield of protein that can be synthesized by pepsin from a given peptic digest is highest when the hydrolyzing action of the pepsin is stopped as soon as all the protein has disappeared from the solution; and that the longer the digest is permitted to contain active enzyme the more the yield diminishes. 2. Exposure of the digest to a hydrogen ion concentration of pH 1.6 in the absence of active enzyme, does not cause a diminution in the amount of protein which can be synthesized from that digest. 3. Synthesis can be effected also in concentrated solutions of isolated fractions of a peptic digest, i.e. of proteose and of peptone. The yields are approximately the same as in similar concentrations of the whole digest, though the proteins so synthesized differ in some respects from those obtained from the whole digest. 4. The cessation of synthesis in any one digest is due to the attainment of equilibrium and not to the complete utilization of available synthesizeable material. The amount of the equilibrium yield, on the other hand, is dependent on the amount of synthesizeable material in the digest. 5. These observations are taken to show that the synthesizeability of a given mixture of protein cleavage products by pepsin depends upon its possession of a special complex in these products. This complex appears as a result of the primary hydrolysis of the protein molecule by pepsin and is decomposed in the slow secondary hydrolysis which ensues as digestion is prolonged

Genetic mechanisms of critical illness in COVID-19.

Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10-8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10-8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 ×  10-12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10-8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte-macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice