Bound Heat No Escape 2 16
In a DMS study, researchers assessed all possible single amino acid variants using a yeast-display system and detected variants that escape either nine neutralizing SARS-CoV-2 mAbs45 or convalescent plasma from 11 individuals taken at two time points after infection39 (shades of green in Fig. 1b). The resulting heat maps provide rich data on the antigenic consequence of RBD mutations, with the plasma escape mutations being of particular interest given that they impact neutralization by polyclonal antibodies of the kind SARS-CoV-2 encounters in infections, with significant levels of immunity acquired through prior exposure or vaccination. Although significant interperson and intraperson heterogeneity in the impact of mutations on neutralization by polyclonal serum has been described, the mutations that reduce antibody binding the most occur at a relatively small number of RBD residues, indicating substantial immunodominance within the RBD39.
Bound Heat No Escape 2 16
Of all RBD residues for which substitutions affected recognition by convalescent sera, DMS identified E484 as being of principal importance, with amino acid changes to K, Q or P reducing neutralization titres by more than an order of magnitude39. E484K has also been identified as an escape mutation that emerges during exposure to mAbs C121 and C144 (ref.40) and convalescent plasma41, and was the only mutation described in one study as able to reduce the neutralizing ability of a combination of mAbs (REGN10989 and REGN10934) to an unmeasurable level47. In an escape mutation study using 19 mAbs, substitutions at E484 emerged more frequently than at any other residue (in response to four mAbs), and each of the four 484 mutants identified (E484A, E484D, E484G and E484K) subsequently conferred resistance to each of four convalescent sera tested48. No other mAb-selected escape mutants escaped each of the four sera, although the mutations K444E, G446V, L452R and F490S escaped three of the four sera tested48.
Among the 5,106 independent substitutions observed in the spike protein (Box 1), 161 are described as affecting recognition by mAbs or polyclonal antibodies in sera, of which 22 are present in more than 100 sequences. On average, variant frequency is higher at amino acid positions where mutations are described as affecting antibody recognition than at positions with no described substitutions of antigenic importance (Supplementary Fig. 1a), and high levels of amino acid substitutions are observed at some amino acid positions where mutations are described as affecting recognition by antibodies in convalescent plasma, including positions 439 and 484. This indicates that, generally, the amino acid positions at which antibody escape mutations have been detected in vitro tolerate mutations at least to some degree in vivo.
Substitutions that individually increase receptor-binding affinity can shift the binding equilibrium between glycoprotein and neutralizing antibodies in favour of a higher-avidity interaction between glycoprotein and the cellular receptor102. The spike amino acid substitution N501Y, which increases ACE2-binding affinity19, has been described as emerging in individuals treated with convalescent plasma, potentially as a means of immune escape.
The deletion or insertion of residues has the potential to alter epitope conformation, diminishing antibody binding. Several deletions in the spike amino-terminal domain (NTD) that affect recognition by neutralizing antibodies have been described41,42. In laboratory experiments, a multiresidue insertion in the spike NTD has been described as emerging and contributing to escape from polyclonal antibodies in convalescent plasma41.
In addition to evaluation of vaccine efficacy against SARS-CoV-2 variants and mutations, the effects of mutations on some mAbs used as therapeutics have been described (Supplementary Table 2). Single mAb treatment can exert a selective pressure that potentially increases the possibility of mutational escape of the targeted antigen. The risk is likely to be reduced with the use of cocktails of two or more mAbs targeting non-overlapping epitopes. REGN-COV2 (Regeneron) (included in the RECOVERY trial in the UK) and AZD7742 (AstraZeneca) are two examples of mAbs cocktails that have been developed93. Importantly, some mutations in the RBM have already been identified in variants which are circulating in the UK (for example, N439K, T478I and V483I) and are likely to impact antigenicity.
Recent studies have shown the potential selective pressure exerted by convalescent plasma and mAb treatments on SARS-CoV-2 evolution in immunocompromised individuals24,25,26. Such circumstances, involving long-term virus shedders, may have contributed to the sporadic emergence of the more heavily mutated variants (for example, seen in the B.1.1.7 and B.1.351 lineages). Given that therapeutics (vaccines and antibody-based therapies) target mainly the SARS-CoV-2 spike protein, the selection pressures that favour the emergence of new variants carrying immune escape mutations generated in chronic infections24,25,26 will be similar to those selecting for mutations that allow reinfections within the wider population27,28,29. Therefore, sequencing of viruses associated with prolonged infections will provide useful information on mutations that could contribute to increased transmissibility or escape from vaccine-mediated immunity.
The collective data on the effect of mutations on vaccines and convalescent serum efficacy show that the polyclonal antibody response is focused on a few immunodominant regions, indicating the high probability of future mutation-mediated escape from host immunity. As antigenically different variants are continuing to emerge, it will become necessary to routinely collect serum samples from vaccinated individuals and from individuals who have been infected with circulating variants of known sequence. Cross-reactive immunity between circulating lineages can be assessed by measuring the ability of sera to neutralize panels of circulating viruses. The systematic surveillance of antigenic SARS-CoV-2 variants will be enhanced by the establishment of a network similar to the WHO-coordinated Global Influenza Surveillance and Response System (GISRS), a collaborative global effort responsible for tracking the antigenic evolution of human influenza viruses and making recommendations on vaccine composition. Modelling approaches to predict the evolutionary trajectories of emerging variants based on an understanding of the phenotypic effects of mutations will assist this process, as is the case for influenza virus94.
(mAbs). Antibodies made by cloning a unique white blood cell, which usually has monovalent binding affinity for a specific epitope. Virus particles can be saturated with mAbs, and the structure can be solved to determine the antibody footprint or mAbs can be used to select for mutations that escape recognition.
Most mass in the univers is in the form of dark matter, how is it that we don't see even the gravitational effects? With huge additional quantities of mass around, planetary orbits should be different, stars should collaps at a different rate, and, finally, black holes should grow at a different rate. (Even the 'darkest' matter should not be able to escape again.) 126.96.36.199 19:18, 15 May 2007 (UTC)Reply[reply]
To cool or heat a 10L tank of liquid quickly I am considering immersing a coil of copper tubing in the liquid and running hot or cold water through it. The problem is, the liquid in the tank is pH 12 (fairly alkaline); I am wondering if the alkaline will cause a lot of copper to go into solution. I am not actually worried about mechanical failure of the tubing, I just would prefer not to add a bunch of copper to my solution.
Any ideas on how to find out effect of alkali on copper? Alternatively, can you suggest a coating for the tubing that wouldn't be too bad of an insulator? Or do you have other ideas for a small scale heat exchanger? ike9898 20:52, 15 May 2007 (UTC)Reply[reply]
He contended that the peripheral heat seal provided between the cover and the back sheet of the sanitary napkin according to E1 cannot act as a barrier to liquid in the meaning of the patent in suit and that the joint between the cover and the second fibrous layer of the laminate according to E2 is made to function as the connecting means for the different layers and is nowhere described to function as a barrier to the liquid.
The respondent further contended that the entire product disclosed in E1 is stabilised by thermobonding and sealed with a peripheral heat seal which hinders the leakage since E1 does not even suggest that the liquid could escape through the seal. The respondent was thus of the opinion that Claim 1 lacked novelty over E1 and, referring to his notice of opposition, he urged that Claim 1 lacked also novelty over both E5 and E6.
"Absorbent article in the form of a single-layer pad or a core of a composite article (102, 118, 199, 203, 211, 230) comprised of a thermobonded mixture of thermoplastic fibers and other absorbent non-thermoplastic fibers, the article having a field and a densified peripheral edge margin (136, 150, 200, 204, 210) along at least a section of the article, characterised in that the peripheral edge margin (136, 150, 200, 204, 210) of fibrous material is densified by ultrasonic or adhesive bonding or thermosetting or heat sealing such that the margin (136, 150, 200, 204, 210) forms a barrier to liquid along at least a section of the article, to substantially impede the leakage of liquid from the pad through the edge margin thereof."
"Absorbent article in the form of a single-layer pad or a core of a composite article (102, 118, 199, 203, 211, 230) comprised of a thermobonded mixture of thermoplastic fibers and other absorbent non-thermoplastic fibers, the article having a field and a densifled peripheral edge margin (136, 150, 200, 204, 210) along at least a section of the article, characterised in that the peripheral edge margin (136, 150, 200, 204, 210) of fibrous material is densified by ultrasonic or adhesive bonding or thermosetting or heat sealing such that the margin (136, 150, 200, 204, 210) forms a barrier to liquid along at least a section of the article, to substantially impede the leakage of liquid from the pad through the edge margin thereof, the densified edge margin (136) being bounded at least in part by an edge (184) of the article which is of lower density than the densified edge margin, the lower density edge (184) being slightly outside the densified edge margin (136) to form a soft edge." 350c69d7ab