• COVID-19
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A common overlapping site on the N-terminal IgV-like domain of human carcinoembryonic antigen (CEA)-related cell adhesion molecules (CEACAMs) is targeted by several important human respiratory pathogens. These include Neisseria meningitidis (Nm) and Haemophilus influenzae (Hi) that can cause disseminated or persistent localized infections. To define the precise structural features that determine the binding of distinct pathogens with CEACAMs, we have undertaken molecular modelling and mutation of the receptor molecules at previously implicated key target residues required for bacterial binding. These include Ser-32, Tyr-34, Val-39, Gln-44 and Gln-89, in addition to Ile-91, the primary docking site for the pathogens. Most, but not all, of these residues located adjacent to each other in a previous N-domain model of human CEACAM1, which was based on REI, CD2 and CD4. In the current studies, we have refined this model based on the mouse CEACAM1 crystal structure, and observe that all of the above residues form an exposed continuous binding region on the N-domain. Examination of the model also suggested that substitution of two of these residues 34 and 89 could affect the accessibility of Ile-91 for ligand binding. By introducing selected mutations at the positions 91, 34 and 89, we confirmed the primary importance of Ile-91 in all bacterial binding to CEACAM1 despite the inter- and intraspecies structural differences between the bacterial CEACAM-binding ligands. The studies further indicated that the efficiency of binding was significantly enhanced for specific strains by mutations such as Y34F and Q89N, which also altered the hierarchy of Nm versus Hi strain binding. These studies imply that distinct polymorphisms in human epithelial CEACAMs have the potential to decrease or increase the risk of infection by the receptor-targeting pathogens.

Background: Emerging and epidemic infectious disease outbreaks are a significant public health problem and global health security threat. As an outbreak begins, epidemiological investigations and traditional public health responses are generally mounted very quickly. However, patient-centred research is usually not prioritised when planning and enacting the response. Instead, the clinical research response occurs subsequent to and separate from the public health response, and is inadequate for evidence-based decision-making at the bedside or in the offices of public health policymakers.Discussion: The deficiencies of the clinical research response to severe acute respiratory syndrome, pandemic influenza, Middle East respiratory syndrome coronavirus and Ebola virus demonstrate that current research models do not adequately inform and improve the quality of clinical care or public health response. Three suggestions for improvements are made. First, integrate the data and sample collection needs for clinical and public health decision-making within a unified framework, combined with a risk-based, rather than a discipline-based, approach to ethical review and consent. Second, develop clinical study methods and tools that are specifically designed to meet the epidemiological and contextual challenges of emerging and epidemic infectious diseases. Third, invest in investigator-led clinical research networks that are primed and incentivised to respond to outbreak infections, and which can call on the support and resources of a central centre of excellence.Conclusions: It is crucial that the field of epidemic science matures to place patients at the heart of the response. This can only be achieved when patient-centred research is integrated in the outbreak response from day one and practical steps are taken to reduce the barriers to the generation of reliable and useful evidence.

Summary Bats and rodents are being increasingly recognized as reservoirs of emerging zoonotic viruses. Various studies have investigated bat viruses in tropical regions, but to date there are no data regarding viruses with zoonotic potential that circulate in bat and rat populations in Viet Nam. To address this paucity of data, we sampled three bat farms and three wet markets trading in rat meat in the Mekong Delta region of southern Viet Nam. Faecal and urine samples were screened for the presence of RNA from paramyxoviruses, coronaviruses and filoviruses. Paramyxovirus RNA was detected in 4 of 248 (1%) and 11 of 222 (4.9%) bat faecal and urine samples, respectively. Coronavirus RNA was detected in 55 of 248 (22%) of bat faecal samples; filovirus RNA was not detected in any of the bat samples. Further, coronavirus RNA was detected in 12 of 270 (4.4%) of rat faecal samples; all samples tested negative for paramyxovirus. Phylogenetic analysis revealed that the bat paramyxoviruses and bat and rat coronaviruses were related to viruses circulating in bat and rodent populations globally, but showed no cross‐species mixing of viruses between bat and rat populations within Viet Nam. Our study shows that potentially novel variants of paramyxoviruses and coronaviruses commonly circulate in bat and rat populations in Viet Nam. Further characterization of the viruses and additional human and animal surveillance is required to evaluate the likelihood of viral spillover and to assess whether these viruses pose a risk to human health.

Golgi anti-apoptotic protein (GAAP), also known as transmembrane Bax inhibitor-1 motif-containing 4 (TMBIM4) or Lifeguard 4 (Lfg4), shares remarkable amino acid conservation with orthologues throughout eukaryotes, prokaryotes and some orthopoxviruses, suggesting a highly conserved function. GAAPs regulate Ca2+levels and fluxes from the Golgi and endoplasmic reticulum, confer resistance to a broad range of apoptotic stimuli, promote cell adhesion and migration via the activation of store-operated Ca2+entry, are essential for the viability of human cells, and affect orthopoxvirus virulence. GAAPs are oligomeric, multi-transmembrane proteins that are resident in Golgi membranes and form cation-selective ion channels that may explain the multiple functions of these proteins. Residues contributing to the ion-conducting pore have been defined and provide the first clues about the mechanistic link between these very different functions of GAAP. Although GAAPs are naturally oligomeric, they can also function as monomers, a feature that distinguishes them from other virus-encoded ion channels that must oligomerize for function. This review summarizes the known functions of GAAPs and discusses their potential importance in disease.

Summary CoV-GLUE is an online web application for the interpretation and analysis of SARS-CoV-2 virus genome sequences, with a focus on amino acid sequence variation. It is based on the GLUE data-centric bioinformatics environment and provides a browsable database of amino acid replacements and coding region indels that have been observed in sequences from the pandemic. Users may also analyse their own SARS-CoV-2 sequences by submitting them to the web application to receive an interactive report containing visualisations of phylogenetic classification and highlighting genomic variation of potentially high impact, for example linked to primer mismatches.Availability and implementation Available at http://cov-glue.cvr.gla.ac.uk. Implemented using GLUE, an open source framework for the development of virus sequence data resources. Contact josh.singer@glasgow.ac.uk

ABSTRACTBackgroundObesity is a major global health problem, and is associated with increased cardiometabolic morbidity and mortality. Protein glycosylation is a frequent postranslational modification, highly responsive to numerous pathophysiological conditions and ageing. The prospect of biological age reduction, by reverting glycosylation changes through metabolic intervention, opens many possibilities. We have investigated whether weight loss interventions affect inflammation- and ageing-associated IgG glycosylation changes, in a longitudinal cohort of bariatric surgery patients. To support potential findings, BMI-related glycosylation changes were monitored in a longitudinal twins cohort.MethodsIgG N-glycans were chromatographically profiled in 37 obese patients, subjected to low-calorie diet, followed by bariatric surgery, across multiple timepoints. Similarly, plasma-derived IgG N-glycan traits were longitudinally monitored in 1,680 participants from the TwinsUK cohort.ResultsLow-calorie diet induced a marked decrease in the levels of IgG N-glycans with bisecting GlcNAc, whose higher levels are usually associated with ageing and inflammatory conditions. Bariatric surgery resulted in extensive alterations of the IgG glycome that accompanied progressive weight loss during one-year follow-up. We observed a significant increase in digalactosylated and sialylated glycans, and a substantial decrease in agalactosylated and core fucosylated IgG glycans. In general, this IgG glycan profile is associated with a younger biological age and reflects an enhanced anti-inflammatory IgG potential. Loss of BMI over a 20 year period in the TwinsUK cohort validated a weight loss-associated agalactosylation decrease and an increase in digalactosylation.ConclusionsAltogether, these findings highlight that weight loss substantially affects IgG N-glycosylation, resulting in reduced biological and immune age.GRAPHICAL ABSTRACTHIGHLIGHTSObesity is associated to inflammation-related agalactosylated and bisected IgG glycoformsIgG galactosylation and sialylation increase after bariatric surgery-induced weight lossProgressive decrease of BMI is associated to increased IgG galactosylation, implying a reduction of biological age

Emerging viruses have the potential to impose substantial mortality, morbidity and economic burdens on human populations. Tracking the spread of infectious diseases to assist in their control has traditionally relied on the analysis of case data gathered as the outbreak proceeds. Here, we describe how many of the key questions in infectious disease epidemiology, from the initial detection and characterization of outbreak viruses, to transmission chain tracking and outbreak mapping, can now be much more accurately addressed using recent advances in virus sequencing and phylogenetics. We highlight the utility of this approach with the hypothetical outbreak of an unknown pathogen, 'Disease X', suggested by the World Health Organization to be a potential cause of a future major epidemic. We also outline the requirements and challenges, including the need for flexible platforms that generate sequence data in real-time, and for these data to be shared as widely and openly as possible.