Mapping SARS-CoV-2 antigenic relationships and serological responses.

During the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, multiple variants escaping preexisting immunity emerged, causing reinfections of previously exposed individuals. Here, we used antigenic cartography to analyze patterns of cross-reactivity among 21 variants and 15 groups of human sera obtained after primary infection with 10 different variants or after messenger RNA (mRNA)-1273 or mRNA-1273.351 vaccination. We found antigenic differences among pre-Omicron variants caused by substitutions at spike-protein positions 417, 452, 484, and 501. Quantifying changes in response breadth over time and with additional vaccine doses, our results show the largest increase between 4 weeks and >3 months after a second dose. We found changes in immunodominance of different spike regions, depending on the variant an individual was first exposed to, with implications for variant risk assessment and vaccine-strain selection.

US National Institutes of Health Prioritization of SARS-CoV-2 Variants.

Since late 2020, SARS-CoV-2 variants have regularly emerged with competitive and phenotypic differences from previously circulating strains, sometimes with the potential to escape from immunity produced by prior exposure and infection. The Early Detection group is one of the constituent groups of the US National Institutes of Health National Institute of Allergy and Infectious Diseases SARS-CoV-2 Assessment of Viral Evolution program. The group uses bioinformatic methods to monitor the emergence, spread, and potential phenotypic properties of emerging and circulating strains to identify the most relevant variants for experimental groups within the program to phenotypically characterize. Since April 2021, the group has prioritized variants monthly. Prioritization successes include rapidly identifying most major variants of SARS-CoV-2 and providing experimental groups within the National Institutes of Health program easy access to regularly updated information on the recent evolution and epidemiology of SARS-CoV-2 that can be used to guide phenotypic investigations.

Mapping SARS-CoV-2 antigenic relationships and serological responses.

During the SARS-CoV-2 pandemic, multiple variants escaping pre-existing immunity emerged, causing concerns about continued protection. Here, we use antigenic cartography to analyze patterns of cross-reactivity among a panel of 21 variants and 15 groups of human sera obtained following primary infection with 10 different variants or after mRNA-1273 or mRNA-1273.351 vaccination. We find antigenic differences among pre-Omicron variants caused by substitutions at spike protein positions 417, 452, 484, and 501. Quantifying changes in response breadth over time and with additional vaccine doses, our results show the largest increase between 4 weeks and >3 months post-2nd dose. We find changes in immunodominance of different spike regions depending on the variant an individual was first exposed to, with implications for variant risk assessment and vaccine strain selection.

PD-1 expression on mouse intratumoral NK cells and its effects on NK cell phenotype.

Although PD-1 was shown to be a hallmark of T cells exhaustion, controversial studies have been reported on the role of PD-1 on NK cells. Here, we found by flow cytometry and single cell RNA sequencing analysis that PD-1 can be expressed on MHC class I-deficient tumor-infiltrating NK cells in vivo. We also demonstrate distinct alterations in the phenotype of PD-1-deficient NK cells and a more mature phenotype which might reduce their capacity to migrate and kill in vivo. Tumor-infiltrating NK cells that express PD-1 were highly associated with the expression of CXCR6. Furthermore, our results demonstrate that PD-L1 molecules in membranes of PD-1-deficient NK cells migrate faster than in NK cells from wild-type mice, suggesting that PD-1 and PD-L1 form cis interactions with each other on NK cells. These data demonstrate that there may be a role for the PD-1/PD-L1 axis in tumor-infiltrating NK cells in vivo.

Analysis of British American Tobacco's questionable use of privilege and protected document claims at the Guildford Depository.

BACKGROUND: Tobacco companies have a documented history of attempting to hide information from public scrutiny, including inappropriate privilege claims. The 1998 Minnesota Consent Judgement created two depositories to provide public access to discovered documents. Users raised concerns about the access conditions and ongoing integrity of the Guildford Depository collection operated until 2015 by British American Tobacco (BAT). METHODS: A metadata search of the Legacy Tobacco Documents Library identified inconsistent privilege claims, and duplicates of documents withheld by BAT from public visitors. A review of the validity of claims, for documents obtained through these searches, was conducted against recognised legal definitions of privilege. FINDINGS: BAT has asserted inappropriate privilege claims over 49% of the documents reviewed (n=63). The quantity of such claims and consistency of the stated rationale for the privilege claims suggest a concerted effort rather than human error. CONCLUSIONS: There was insufficient attention given to the operation of the Guildford Depository by the original plaintiffs, including to the subsequent use of privilege claims. Appropriate access to these documents, commensurate with the terms of legal settlements creating the collection, was critical given their public interest value for enhancing understanding of industry strategies and activities, informing of policy interventions, and for holding the industry to account. Future legal settlements should prevent defendants from subsequently withholding disclosed documents, aside from those legitimately privileged, from public view. Control of publicly disclosed documents should not be placed back into the hands of defendant tobacco companies. Plaintiffs also need to invest adequate resources into policing claims of legal privilege.

To 'enable our legal product to compete effectively with the transit market': British American Tobacco's strategies in Thailand following the 1990 GATT dispute.

The opening of the Thai tobacco market, following action brought by the US Trade Representative under the General Agreement on Tariffs and Trade, is seen as a key case study of the tensions between trade and health policy. Interpretations of the dispute cast it, either as an example of how trade agreements undermine national policy-making, or how governments can adopt effective public health protections compliant with international trade rules. As a UK-based company, British American Tobacco has been regarded as peripheral to this dispute. This paper argues that its close monitoring of the illegal trade during this period, the role of smuggling in the company's global business strategy, and its management of the relative supply and pricing of legal and illegal products after market opening provide a fuller understanding of the interests and roles of transnational tobacco companies and the government in this dispute. The findings have important policy implications, notably the role of effective governance in countries facing pressure to open their tobacco sectors, need to better understand corporate-level activities within an increasingly globalised tobacco industry, and need to address the intertwined legal and illegal trade in implementing the WHO Framework Convention on Tobacco Control Protocol to Eliminate Illicit Trade in Tobacco Products.

Exploitation of the catalytic site and 150 cavity for design of influenza A neuraminidase inhibitors.

We report here the exploitation of the 150 cavity in the active site of influenza A viral neuraminidases for the design of novel C-6 triazole-containing Tamiflu derivatives. A general and convenient synthetic route was developed by utilizing a highly substituted cyclic Baylis-Hillman acetate as an active precursor for azide substitution via suprafacial allylic azide [3,3]-sigmatropic rearrangement. Virus replication inhibitory assays in vitro of these triazole derivatives containing either an amino or guanidino function indicated that the guanidinium compound showed the higher efficacy against a strain with N2 subtype at a concentration of 2 × 10(-5) M but did not inhibit replication of a strain with N1 subtype even at a concentration of 10(-4) M. In order to probe the nature of the enzyme-inhibitor interactions, molecular dynamics simulations were performed on complexes of these compounds with different neuraminidase enzymes. The results indicated that the candidate inhibitors occupy both the 150 cavity and catalytic site but with alternating occupancy.

The influence of 150-cavity binders on the dynamics of influenza A neuraminidases as revealed by molecular dynamics simulations and combined clustering.

Neuraminidase inhibitors are the main pharmaceutical agents employed for treatments of influenza infections. The neuraminidase structures typically exhibit a 150-cavity, an exposed pocket that is adjacent to the catalytic site. This site offers promising additional contact points for improving potency of existing pharmaceuticals, as well as generating entirely new candidate inhibitors. Several inhibitors based on known compounds and designed to interact with 150-cavity residues have been reported. However, the dynamics of any of these inhibitors remains unstudied and their viability remains unknown. This work reports the outcome of long-term, all-atom molecular dynamics simulations of four such inhibitors, along with three standard inhibitors for comparison. Each is studied in complex with four representative neuraminidase structures, which are also simulated in the absence of ligands for comparison, resulting in a total simulation time of 9.6 µs. Our results demonstrate that standard inhibitors characteristically reduce the mobility of these dynamic proteins, while the 150-binders do not, instead giving rise to many unique conformations. We further describe an improved RMSD-based clustering technique that isolates these conformations--the structures of which are provided to facilitate future molecular docking studies--and reveals their interdependence. We find that this approach confers many advantages over previously described techniques, and the implications for rational drug design are discussed.

Product liability.

Product liability litigation has made important contributions to tobacco control, especially by uncovering incriminating industry documents and publicizing product dangers and industry misconduct. WHO Framework Convention on Tobacco Control (FCTC) Article 19 encourages Parties to strengthen legal procedures to facilitate these lawsuits and to establish mechanisms for mutual assistance. Creative lawyers will continue to find ways to bring the tobacco industry to justice in forums around the world.

Perceptions of industry responsibility and tobacco control policy by US tobacco company executives in trial testimony.

OBJECTIVE: Trial testimony from the United States provides a unique opportunity to examine strategies of the American tobacco industry. This paper examines congruence between the arguments for tobacco control policy presented by representatives of the American tobacco industry at trial and the stages of responsibility associated with corporate social responsibility principles in other industries. DATA SOURCES: Trial testimony collected and coded by the Deposition and Trial Testimony Archive (DATTA). STUDY SELECTION: All available testimony was gathered from representative senior staff from major tobacco companies: Brown & Williamson, Philip Morris, RJ Reynolds, and Liggett. DATA EXTRACTION: Transcripts from each witness selected were collected and imported in text format into WinMax, a qualitative data program. The documents were searched for terms relating to tobacco control policies, and relevant terms were extracted. A hand search of the documents was also conducted by reading through the testimony. Inferred responsibility for various tobacco control policies (health information, second-hand smoking, youth smoking) was coded. DATA SYNTHESIS: The level of responsibility for tobacco control policy varied according to the maturity of the issue. For emerging issues, US tobacco company representatives expressed defensiveness while, for more mature issues, such as youth smoking, they showed increased willingness to deal with the issue. This response to social issues is consistent with corporate social responsibility strategies in other industries. CONCLUSION: While other industries use corporate social responsibility programmes to address social issues to protect their core business product, the fundamental social issue with tobacco is the product itself. As such, the corporate nature of tobacco companies is a structural obstacle to reducing harm caused by tobacco use.

Movie moguls: British American Tobacco's covert strategy to promote cigarettes in Eastern Europe.

BACKGROUND: Though the cigarette companies have long publicly denied paying for product placement in films, the documentary evidence from the 1950s-1980s overwhelmingly suggests otherwise. METHODS: Approximately 800,000 pages of previously secret internal corporate British American Tobacco Company documents were reviewed at the Minnesota Tobacco Document Depository from March 2003 through May 2005. Documents were also searched online at the various tobacco document collections between February 2004 and November 2004. RESULTS: A small collection of internal corporate documents from British American Tobacco show that in the late 1990s the company evaluated investing in a movie destined for Eastern Europe. By being an investor, BAT could influence the alteration of the movie script to promote BAT's brands, thus providing marketing opportunities without a clear violation of movie product placement restrictions. CONCLUSION: Future protocols to the WHO Framework Convention on Tobacco Control should seek to curtail more than just payment for tobacco product placement. More restrictive provisions will be needed to hinder creative strategies by the tobacco industry to continue tobacco promotion and trademark diversification through movies.

Playing hide-and-seek with the tobacco industry.

Despite many peer-reviewed works that draw on tobacco industry documents that have now been made public, questions remain about how complete a picture has emerged. We present a conceptual framework that identifies and evaluates tobacco industry efforts to conceal information. Widespread document destruction like that in recent litigation in Australia is just one of more than a dozen tobacco industry efforts to prevent access, or at least timely access, to documents. Industry efforts range from small, locally employed initiatives to company-wide tactics. Some efforts, such as using "oral only" procedures, scrambling telephone lines, or involving lawyers in scientific projects, are preemptive. Others seek to deal with already existing documents by invoking bogus claims of legal privilege, stipulating "read then destroy" for memos, and rewriting problematic memos. That evidence of concealment has, in fact, been found in tobacco company archives attests to the futility of attempting to control the flow of millions of pieces of paper among tens of thousands of employees. However, researchers have yet to reveal the full story: We know of the industry's failures in concealing information, but not its successes. The industry's objective is not destruction of information per se, but prevention of public disclosure of that information. Exposing the tobacco industry's many approaches to concealment provides greater insight into companies' intentions and potential means for stripping away that concealment.

Big tobacco is watching: British American Tobacco's surveillance and information concealment at the Guildford depository.

The 1998 State of Minnesota legal settlement with the tobacco industry required British American Tobacco (BAT) to provide public access to the 8 million pages housed in its document depository located near Guildford, UK, and to any company documents sent to the Minnesota depository. While the Minnesota depository is managed by an independent third party, BAT's Guildford depository is run by the company itself. Starkly different from the Minnesota depository, at the Guildford depository it is extraordinarily more difficult to access, search, and obtain requested documents. BAT's approach to running the Guildford depository, in our view, amounts to concealing what is supposed to be public information. Newly produced BAT documents from subsequent litigation, dating from 1996 to 2001 disclose the company's efforts to gather intelligence on visitors and their work. We believe that BAT has acted to make access to information more difficult by delaying document production requested by public visitors and refusing to supply requested documents in an electronic format despite, in the company's own words, the establishment of "big time imaging" capabilities at the Guildford depository. During testimony in 2000, then BAT Chairman, Martin Broughton stated to the UK House of Commons Health Select Committee that the scanning and subsequent placement of the Guildford collection online "would be an extreme effort for absolutely no purpose whatsoever", stating that "there is no indication to me that serious researchers are showing any interest in the papers em leader ". New documents show that not only did the company recognise the importance of research undertaken by visitors, but also invested substantial resources and undertook numerous scanning projects during that time. The vulnerability of this important resource is demonstrated by the decreased number of files listed on the electronic database and the inadvertent deletion of an audio tape housed at the depository. With regard to intelligence gathering, BAT's law firm reported to BAT on the daily activities of depository visitors. Despite assurances to the contrary, these depository visitor reports show that BAT apparently tracked the database searches of a visitor. The company also tracked the physical movement of visitors and, in at least one instance, observed and noted the personal mobile phone use of a visitor. These activities raise ethical issues about BAT and/or its solicitors observing the work of lawyers and researchers representing health and government bodies. Given this new evidence, we assert that BAT is incapable of operating its depository in the spirit of the Minnesota settlement and should, therefore, be divorced from its operation. Accordingly, we recommend that the company provide its entire document collection electronically to interested parties thus allowing greater access to the public-health community as has been done in the USA.