ADCC Develops Over Time during Persistent Infection with Live-Attenuated SIV and Is Associated with Complete Protection against SIV(mac)251 Challenge

Live-attenuated strains of simian immunodeficiency virus (SIV) routinely confer apparent sterilizing immunity against pathogenic SIV challenge in rhesus macaques. Understanding the mechanisms of protection by live-attenuated SIV may provide important insights into the immune responses needed for protection against HIV-1. Here we investigated the development of antibodies that are functional against neutralization-resistant SIV challenge strains, and tested the hypothesis that these antibodies are associated with protection. In the absence of detectable neutralizing antibodies, Env-specific antibody-dependent cell-mediated cytotoxicity (ADCC) emerged by three weeks after inoculation with SIVDeltanef, increased progressively over time, and was proportional to SIVDeltanef replication. Persistent infection with SIVDeltanef elicited significantly higher ADCC titers than immunization with a non-persistent SIV strain that is limited to a single cycle of infection. ADCC titers were higher against viruses matched to the vaccine strain in Env, but were measurable against viruses expressing heterologous Env proteins. In two separate experiments, which took advantage of either the strain-specificity or the time-dependent maturation of immunity to overcome complete protection against SIV(mac)251 challenge, measures of ADCC activity were higher among the SIVDeltanef-inoculated macaques that remained uninfected than among those that became infected. These observations show that features of the antibody response elicited by SIVDeltanef are consistent with hallmarks of protection by live-attenuated SIV, and reveal an association between Env-specific antibodies that direct ADCC and apparent sterilizing protection by SIVDeltanef

Renormalization group flows and continual Lie algebras

We study the renormalization group flows of two-dimensional metrics in sigma models and demonstrate that they provide a continual analogue of the Toda field equations based on the infinite dimensional algebra G(d/dt;1). The resulting Toda field equation is a non-linear generalization of the heat equation, which is integrable in target space and shares the same dissipative properties in time. We provide the general solution of the renormalization group flows in terms of free fields, via Backlund transformations, and present some simple examples that illustrate the validity of their formal power series expansion in terms of algebraic data. We study in detail the sausage model that arises as geometric deformation of the O(3) sigma model, and give a new interpretation to its ultra-violet limit by gluing together two copies of Witten's two-dimensional black hole in the asymptotic region. We also provide some new solutions that describe the renormalization group flow of negatively curved spaces in different patches, which look like a cane in the infra-red region. Finally, we revisit the transition of a flat cone C/Z_n to the plane, as another special solution, and note that tachyon condensation in closed string theory exhibits a hidden relation to the infinite dimensional algebra G(d/dt;1) in the regime of gravity. Its exponential growth holds the key for the construction of conserved currents and their systematic interpretation in string theory, but they still remain unknown.Comment: latex, 73pp including 14 eps fig

The Metagenome of an Anaerobic Microbial Community Decomposing Poplar Wood Chips

This study describes the composition and metabolic potential of a lignocellulosic biomass degrading community that decays poplar wood chips under anaerobic conditions. We examined the community that developed on poplar biomass in a non-aerated bioreactor over the course of a year, with no microbial inoculation other than the naturally occurring organisms on the woody material. The composition of this community contrasts in important ways with biomass-degrading communities associated with higher organisms, which have evolved over millions of years into a symbiotic relationship. Both mammalian and insect hosts provide partial size reduction, chemical treatments (low or high pH environments), and complex enzymatic ‘secretomes’ that improve microbial access to cell wall polymers. We hypothesized that in order to efficiently degrade coarse untreated biomass, a spontaneously assembled free-living community must both employ alternative strategies, such as enzymatic lignin depolymerization, for accessing hemicellulose and cellulose and have a much broader metabolic potential than host-associated communities. This would suggest that such a community would make a valuable resource for finding new catalytic functions involved in biomass decomposition and gaining new insight into the poorly understood process of anaerobic lignin depolymerization. Therefore, in addition to determining the major players in this community, our work specifically aimed at identifying functions potentially involved in the depolymerization of cellulose, hemicelluloses, and lignin, and to assign specific roles to the prevalent community members in the collaborative process of biomass decomposition. A bacterium similar to Magnetospirillum was identified among the dominant community members, which could play a key role in the anaerobic breakdown of aromatic compounds. We suggest that these compounds are released from the lignin fraction in poplar hardwood during the decay process, which would point to lignin-modification or depolymerization under anaerobic conditions

Variation in the provision and practice of implant-based breast reconstruction in the UK: Results from the iBRA national practice questionnaire

Introduction The introduction of biological and synthetic meshes has revolutionised the practice of implant-based breast reconstruction (IBBR) but evidence for effectiveness is lacking. The iBRA (implant Breast Reconstruction evAluation) study is a national trainee-led project that aims to explore the practice and outcomes of IBBR to inform the design of a future trial. We report the results of the iBRA National Practice Questionnaire (NPQ) which aimed to comprehensively describe the provision and practice of IBBR across the UK. Methods A questionnaire investigating local practice and service provision of IBBR developed by the iBRA Steering Group was completed by trainee and consultant leads at breast and plastic surgical units across the UK. Summary data for each survey item were calculated and variation between centres and overall provision of care examined. Results 81 units within 79 NHS-hospitals completed the questionnaire. Units offered a range of reconstructive techniques, with IBBR accounting for 70% (IQR:50–80%) of participating units' immediate procedures. Units on average were staffed by 2.5 breast surgeons (IQR:2.0–3.0) and 2.0 plastic surgeons (IQR:1.0–3.0) performing 35 IBBR cases per year (IQR:20-50). Variation was demonstrated in the provision of novel different techniques for IBBR especially the use of biological (n = 62) and synthetic (n = 25) meshes and in patient selection for these procedures. Conclusions The iBRA-NPQ has demonstrated marked variation in the provision and practice of IBBR in the UK. The prospective audit phase of the iBRA study will determine the safety and effectiveness of different approaches to IBBR and allow evidence-based best practice to be explored

Genomic reconstruction of the SARS-CoV-2 epidemic in England.

The evolution of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus leads to new variants that warrant timely epidemiological characterization. Here we use the dense genomic surveillance data generated by the COVID-19 Genomics UK Consortium to reconstruct the dynamics of 71 different lineages in each of 315 English local authorities between September 2020 and June 2021. This analysis reveals a series of subepidemics that peaked in early autumn 2020, followed by a jump in transmissibility of the B.1.1.7/Alpha lineage. The Alpha variant grew when other lineages declined during the second national lockdown and regionally tiered restrictions between November and December 2020. A third more stringent national lockdown suppressed the Alpha variant and eliminated nearly all other lineages in early 2021. Yet a series of variants (most of which contained the spike E484K mutation) defied these trends and persisted at moderately increasing proportions. However, by accounting for sustained introductions, we found that the transmissibility of these variants is unlikely to have exceeded the transmissibility of the Alpha variant. Finally, B.1.617.2/Delta was repeatedly introduced in England and grew rapidly in early summer 2021, constituting approximately 98% of sampled SARS-CoV-2 genomes on 26 June 2021

Constitutional Fideism

Sanford Levinson. Constitutional Faith. Princeton, N.J.: Princeton University Press, 1988. Pp. xii, 250. $19.95. Pencil in a question mark after the title. Sanford Levinson means to question whether faith in the Constitution, or indeed in anything, is possible. At the end of his book, exhausted by his doubts and by the effort to overcome them, he does subscribe to the Constitution, signing ceremoniously less as a proud citizen than as a privileged member of the American class structure (p. 193) who feels guilty about his privileges and hopes the Constitution can be used to subvert them. If this hope comes true, Levinson\u27s faith that the Constitution is more than a mere endorsement and concealment of the American class structure will be justified. But there is no ground for this faith, he believes, in either reason or revelation. Levinson\u27s constitutional faith is like religion in not being rationally supportable, but unlike religion in not being conveyed to us from on high. Since there is no ground for faith, how can there be ground for guilt? But Levinson\u27s guilt is his second skin. He needs his faith to tend his guilt, not absolve it. Better, then, that his faith not be justified. Constitutional faith, as Levinson presents it, substitutes for a nonexistent common good, and even for morality as a whole, which is also nonexistent. His first chapter is on the Constitution in American civil religion, where he develops Catholic and Protestant views of the Constitution. His second examines the morality of the Constitution, particularly the moral difficulty of respecting a document that seemed to protect slavery. The third is on loyalty oaths and what they mean; the fourth is on the naturalization of citizens and whether the attachment of such citizens to the Constitution can be defined; and the fifth, about Levinson\u27s own status as professor of law, considers whether Law Schools should teach respect for the American Constitution (not too much, is his answer)