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An Interdisciplinary Research Centre at the University of Cambridge
 

Suppression of innate immunity by the vaccinia virus protein N1 promotes skin microbiota expansion and increased immune infiltration following vaccination

Tue, 07/02/2023 - 11:00

J Gen Virol. 2022 Nov;103(11). doi: 10.1099/jgv.0.001814.

ABSTRACT

Vaccinia virus (VACV) protein N1 is an intracellular immunomodulator that contributes to virus virulence via inhibition of NF-κB. Intradermal infection with a VACV lacking gene N1L (vΔN1) results in smaller skin lesions than infection with wild-type virus (WT VACV), but the impact of N1 deletion on the local microbiota as well as the innate and cellular immune responses in infected ear tissue is mostly uncharacterized. Here, we analysed the bacterial burden and host immune response at the site of infection and report that the presence of protein N1 correlated with enhanced expansion of skin microbiota, even before lesion development. Furthermore, early after infection (days 1-3), prior to lesion development, the levels of inflammatory mediators were higher in vΔN1-infected tissue compared to WT VACV infection. In contrast, infiltration of ear tissue with myeloid and lymphoid cells was greater after WT VACV infection and there was significantly greater secondary bacterial infection that correlated with greater lesion size. We conclude that a more robust innate immune response to vΔN1 infection leads to better control of virus replication, less bacterial growth and hence an overall reduction of tissue damage and lesion size. This analysis shows the potent impact of a single viral immunomodulator on the host immune response and the pathophysiology of VACV infection in the skin.

PMID:36748513 | DOI:10.1099/jgv.0.001814

How public health authorities can use pathogen genomics in health protection practice: a consensus-building Delphi study conducted in the United Kingdom

Mon, 06/02/2023 - 11:00

Microb Genom. 2023 Feb;9(2). doi: 10.1099/mgen.0.000912.

ABSTRACT

Pathogen sequencing guided understanding of SARS-CoV-2 evolution during the COVID-19 pandemic. Many health systems developed pathogen genomics services to monitor SARS-CoV-2. There are no agreed guidelines about how pathogen genomic information should be used in public health practice. We undertook a modified Delphi study in three rounds to develop expert consensus statements about how genomic information should be used. Our aim was to inform health protection policy, planning and practice. Participants were from organisations that produced or used pathogen genomics information in the United Kingdom. The first round posed questions derived from a rapid literature review. Responses informed statements for the subsequent rounds. Consensus was accepted when 70 % or more of the responses were strongly agree/agree, or 70 % were disagree/strongly disagree on the five-point Likert scale. Consensus was achieved in 26 (96 %) of 27 statements. We grouped the statements into six categories: monitoring the emergence of new variants; understanding the epidemiological context of genomic data; using genomic data in outbreak risk assessment and risk management; prioritising the use of limited sequencing capacity; sequencing service performance; and sequencing service capability. The expert consensus statements will help guide public health authorities and policymakers to integrate pathogen genomics in health protection practice.

PMID:36745548 | DOI:10.1099/mgen.0.000912

Insights into azalomycin F assembly-line contribute to evolution-guided polyketide synthase engineering and identification of intermodular recognition

Sat, 04/02/2023 - 11:00

Nat Commun. 2023 Feb 4;14(1):612. doi: 10.1038/s41467-023-36213-9.

ABSTRACT

Modular polyketide synthase (PKS) is an ingenious core machine that catalyzes abundant polyketides in nature. Exploring interactions among modules in PKS is very important for understanding the overall biosynthetic process and for engineering PKS assembly-lines. Here, we show that intermodular recognition between the enoylreductase domain ER1/2 inside module 1/2 and the ketosynthase domain KS3 inside module 3 is required for the cross-module enoylreduction in azalomycin F (AZL) biosynthesis. We also show that KS4 of module 4 acts as a gatekeeper facilitating cross-module enoylreduction. Additionally, evidence is provided that module 3 and module 6 in the AZL PKS are evolutionarily homologous, which makes evolution-oriented PKS engineering possible. These results reveal intermodular recognition, furthering understanding of the mechanism of the PKS assembly-line, thus providing different insights into PKS engineering. This also reveals that gene duplication/conversion and subsequent combinations may be a neofunctionalization process in modular PKS assembly-lines, hence providing a different case for supporting the investigation of modular PKS evolution.

PMID:36739290 | DOI:10.1038/s41467-023-36213-9

Using genetic association data to guide drug discovery and development: Review of methods and applications

Fri, 03/02/2023 - 11:00

Am J Hum Genet. 2023 Feb 2;110(2):195-214. doi: 10.1016/j.ajhg.2022.12.017.

ABSTRACT

Evidence on the validity of drug targets from randomized trials is reliable but typically expensive and slow to obtain. In contrast, evidence from conventional observational epidemiological studies is less reliable because of the potential for bias from confounding and reverse causation. Mendelian randomization is a quasi-experimental approach analogous to a randomized trial that exploits naturally occurring randomization in the transmission of genetic variants. In Mendelian randomization, genetic variants that can be regarded as proxies for an intervention on the proposed drug target are leveraged as instrumental variables to investigate potential effects on biomarkers and disease outcomes in large-scale observational datasets. This approach can be implemented rapidly for a range of drug targets to provide evidence on their effects and thus inform on their priority for further investigation. In this review, we present statistical methods and their applications to showcase the diverse opportunities for applying Mendelian randomization in guiding clinical development efforts, thus enabling interventions to target the right mechanism in the right population group at the right time. These methods can inform investigators on the mechanisms underlying drug effects, their related biomarkers, implications for the timing of interventions, and the population subgroups that stand to gain the most benefit. Most methods can be implemented with publicly available data on summarized genetic associations with traits and diseases, meaning that the only major limitations to their usage are the availability of appropriately powered studies for the exposure and outcome and the existence of a suitable genetic proxy for the proposed intervention.

PMID:36736292 | DOI:10.1016/j.ajhg.2022.12.017

LRRC15 mediates an accessory interaction with the SARS-CoV-2 spike protein

Fri, 03/02/2023 - 11:00

PLoS Biol. 2023 Feb 3;21(2):e3001959. doi: 10.1371/journal.pbio.3001959. eCollection 2023 Feb.

ABSTRACT

The interactions between Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and human host factors enable the virus to propagate infections that lead to Coronavirus Disease 2019 (COVID-19). The spike protein is the largest structural component of the virus and mediates interactions essential for infection, including with the primary angiotensin-converting enzyme 2 (ACE2) receptor. We performed two independent cell-based systematic screens to determine whether there are additional proteins by which the spike protein of SARS-CoV-2 can interact with human cells. We discovered that in addition to ACE2, expression of LRRC15 also causes spike protein binding. This interaction is distinct from other known spike attachment mechanisms such as heparan sulfates or lectin receptors. Measurements of orthologous coronavirus spike proteins implied the interaction was functionally restricted to SARS-CoV-2 by accessibility. We localized the interaction to the C-terminus of the S1 domain and showed that LRRC15 shares recognition of the ACE2 receptor binding domain. From analyzing proteomics and single-cell transcriptomics, we identify LRRC15 expression as being common in human lung vasculature cells and fibroblasts. Levels of LRRC15 were greatly elevated by inflammatory signals in the lungs of COVID-19 patients. Although infection assays demonstrated that LRRC15 alone is not sufficient to permit viral entry, we present evidence that it can modulate infection of human cells. This unexpected interaction merits further investigation to determine how SARS-CoV-2 exploits host LRRC15 and whether it could account for any of the distinctive features of COVID-19.

PMID:36735681 | DOI:10.1371/journal.pbio.3001959

Using 'sentinel' plants to improve early detection of invasive plant pathogens

Thu, 02/02/2023 - 11:00

PLoS Comput Biol. 2023 Feb 2;19(2):e1010884. doi: 10.1371/journal.pcbi.1010884. Online ahead of print.

ABSTRACT

Infectious diseases of plants present an ongoing and increasing threat to international biosecurity, with wide-ranging implications. An important challenge in plant disease management is achieving early detection of invading pathogens, which requires effective surveillance through the implementation of appropriate monitoring programmes. However, when monitoring relies on visual inspection as a means of detection, surveillance is often hindered by a long incubation period (delay from infection to symptom onset) during which plants may be infectious but not displaying visible symptoms. 'Sentinel' plants-alternative susceptible host species that display visible symptoms of infection more rapidly-could be introduced to at-risk populations and included in monitoring programmes to act as early warning beacons for infection. However, while sentinel hosts exhibit faster disease progression and so allow pathogens to be detected earlier, this often comes at a cost: faster disease progression typically promotes earlier onward transmission. Here, we construct a computational model of pathogen transmission to explore this trade-off and investigate how including sentinel plants in monitoring programmes could facilitate earlier detection of invasive plant pathogens. Using Xylella fastidiosa infection in Olea europaea (European olive) as a current high profile case study, for which Catharanthus roseus (Madagascan periwinkle) is a candidate sentinel host, we apply a Bayesian optimisation algorithm to determine the optimal number of sentinel hosts to introduce for a given sampling effort, as well as the optimal division of limited surveillance resources between crop and sentinel plants. Our results demonstrate that including sentinel plants in monitoring programmes can reduce the expected prevalence of infection upon outbreak detection substantially, increasing the feasibility of local outbreak containment.

PMID:36730434 | DOI:10.1371/journal.pcbi.1010884

Genome-wide host-pathogen analyses reveal genetic interaction points in tuberculosis disease

Wed, 01/02/2023 - 11:00

Nat Commun. 2023 Feb 1;14(1):549. doi: 10.1038/s41467-023-36282-w.

ABSTRACT

The genetics underlying tuberculosis (TB) pathophysiology are poorly understood. Human genome-wide association studies have failed so far to reveal reproducible susceptibility loci, attributed in part to the influence of the underlying Mycobacterium tuberculosis (Mtb) bacterial genotype on the outcome of the infection. Several studies have found associations of human genetic polymorphisms with Mtb phylo-lineages, but studies analysing genome-genome interactions are needed. By implementing a phylogenetic tree-based Mtb-to-human analysis for 714 TB patients from Thailand, we identify eight putative genetic interaction points (P < 5 × 10-8) including human loci DAP and RIMS3, both linked to the IFNγ cytokine and host immune system, as well as FSTL5, previously associated with susceptibility to TB. Many of the corresponding Mtb markers are lineage specific. The genome-to-genome analysis reveals a complex interactome picture, supports host-pathogen adaptation and co-evolution in TB, and has potential applications to large-scale studies across many TB endemic populations matched for host-pathogen genomic diversity.

PMID:36725857 | DOI:10.1038/s41467-023-36282-w

Two distinct long-range synaptic complexes promote different aspects of end processing prior to repair of DNA breaks by non-homologous end joining

Wed, 01/02/2023 - 11:00

Mol Cell. 2023 Jan 24:S1097-2765(23)00032-1. doi: 10.1016/j.molcel.2023.01.012. Online ahead of print.

ABSTRACT

Non-homologous end joining is the major double-strand break repair (DSBR) pathway in mammals. DNA-PK is the hub and organizer of multiple steps in non-homologous end joining (NHEJ). Recent high-resolution structures show how two distinct NHEJ complexes "synapse" two DNA ends. One complex includes a DNA-PK dimer mediated by XLF, whereas a distinct DNA-PK dimer forms via a domain-swap mechanism where the C terminus of Ku80 from one DNA-PK protomer interacts with another DNA-PK protomer in trans. Remarkably, the distance between the two synapsed DNA ends in both dimers is the same (∼115 Å), which matches the distance observed in the initial description of an NHEJ long-range synaptic complex. Here, a mutational strategy is used to demonstrate distinct cellular function(s) of the two dimers: one promoting fill-in end processing, while the other promotes DNA end resection. Thus, the specific DNA-PK dimer formed (which may be impacted by DNA end structure) dictates the mechanism by which ends will be made ligatable.

PMID:36724784 | DOI:10.1016/j.molcel.2023.01.012

Peroxide-cleavable linkers for antibody-drug conjugates

Wed, 01/02/2023 - 11:00

Chem Commun (Camb). 2023 Jan 26. doi: 10.1039/d2cc06677g. Online ahead of print.

ABSTRACT

Antibody-drug conjugates containing peroxide-cleavable arylboronic acid linkers are described, which target the high levels of reactive oxygen species (ROS) in cancer. The arylboronic acid linkers rapidly release a payload in the presence of hydrogen peroxide, but remain stable in plasma. Anti-HER2 and PD-L1 peroxide-cleavable ADCs exhibited potent cytotoxicity in vitro.

PMID:36722863 | DOI:10.1039/d2cc06677g

Reduced circulating BMP9 and pBMP10 in hospitalized COVID-19 patients

Wed, 01/02/2023 - 11:00

Pulm Circ. 2023 Jan 1;13(1):e12192. doi: 10.1002/pul2.12192. eCollection 2023 Jan.

ABSTRACT

Similar to other causes of acute respiratory distress syndrome, coronavirus disease 2019 (COVID-19) is characterized by the aberrant expression of vascular injury biomarkers. We present the first report that circulating plasma bone morphogenetic proteins (BMPs), BMP9 and pBMP10, involved in vascular protection, are reduced in hospitalized patients with COVID-19.

PMID:36721385 | PMC:PMC9881210 | DOI:10.1002/pul2.12192

Developing Wolbachia-based disease interventions for an extreme environment

Tue, 31/01/2023 - 11:00

PLoS Pathog. 2023 Jan 31;19(1):e1011117. doi: 10.1371/journal.ppat.1011117. Online ahead of print.

ABSTRACT

Aedes aegypti mosquitoes carrying self-spreading, virus-blocking Wolbachia bacteria are being deployed to suppress dengue transmission. However, there are challenges in applying this technology in extreme environments. We introduced two Wolbachia strains into Ae. aegypti from Saudi Arabia for a release program in the hot coastal city of Jeddah. Wolbachia reduced infection and dissemination of dengue virus (DENV2) in Saudi Arabian mosquitoes and showed complete maternal transmission and cytoplasmic incompatibility. Wolbachia reduced egg hatch under a range of environmental conditions, with the Wolbachia strains showing differential thermal stability. Wolbachia effects were similar across mosquito genetic backgrounds but we found evidence of local adaptation, with Saudi Arabian mosquitoes having lower egg viability but higher adult desiccation tolerance than Australian mosquitoes. Genetic background effects will influence Wolbachia invasion dynamics, reinforcing the need to use local genotypes for mosquito release programs, particularly in extreme environments like Jeddah. Our comprehensive characterization of Wolbachia strains provides a foundation for Wolbachia-based disease interventions in harsh climates.

PMID:36719928 | DOI:10.1371/journal.ppat.1011117

Characterization of the Culturable Sporobiota of Spanish Olive Groves and Its Tolerance toward Environmental Challenges

Tue, 31/01/2023 - 11:00

Microbiol Spectr. 2023 Jan 31:e0401322. doi: 10.1128/spectrum.04013-22. Online ahead of print.

ABSTRACT

Olive agriculture presents an integral economic and social pillar of the Mediterranean region with 95% of the world's olive tree population concentrated in this area. A diverse ecosystem consisting of fungi, archaea, viruses, protozoa, and microbial communities-the soil microbiome-plays a central role in maintaining healthy soils while keeping up productivity. Spore-forming organisms (i.e., the sporobiota) have been identified as one of the predominant communities of the soil microbiome and are known for the wide variety of antimicrobial properties and extraordinary resistance. Hence, the aim of this work was to determine the culturable sporobiota of Spanish olive orchards and characterize its phenotypic properties toward common environmental challenges. A collection of 417 heat-resistant bacteria were isolated from five Spanish olive orchards. This collective was termed the "olive sporobiota." Rep-PCR clustering of representative isolates revealed that they all belonged to the group of Bacillus spp., or closely related species, showing a great variety of species and strains. Representative isolates showed susceptibility to common antibiotics, as well as good resistance to heavy metal exposure, with an order of metal tolerance determined as iron > copper > nickel > manganese > zinc > cadmium. Finally, we showed that the application of mineral fertilizer can in several cases enhance bacterial growth and thus potentially increase the relative proportion of the sporobiota in the olive grove ecosystem. In summary, the identification of the culturable olive sporobiota increases our understanding of the microbial diversity in Spanish olive groves, while tolerance and resistance profiles provide important insights into the phenotypic characteristics of the microbial community. IMPORTANCE Microbial communities are a key component of healthy soils. Spore-forming microorganisms represent a large fraction of this community-termed the "sporobiota"-and play a central role in creating a conducive environment for plant growth and food production. In addition, given their unique features, such as extraordinary stability and antimicrobial properties, members of the sporobiota present interesting candidates for biotechnological applications, such as sustainable plant protection products or in a clinical setting. For this, however, more information is needed on the spore-forming community of agricultural installations, ultimately promoting a transition toward a more sustainable agriculture.

PMID:36719235 | DOI:10.1128/spectrum.04013-22

A patient-centric modeling framework captures recovery from SARS-CoV-2 infection

Mon, 30/01/2023 - 11:00

Nat Immunol. 2023 Jan 30. doi: 10.1038/s41590-022-01380-2. Online ahead of print.

ABSTRACT

The biology driving individual patient responses to severe acute respiratory syndrome coronavirus 2 infection remains ill understood. Here, we developed a patient-centric framework leveraging detailed longitudinal phenotyping data and covering a year after disease onset, from 215 infected individuals with differing disease severities. Our analyses revealed distinct 'systemic recovery' profiles, with specific progression and resolution of the inflammatory, immune cell, metabolic and clinical responses. In particular, we found a strong inter-patient and intra-patient temporal covariation of innate immune cell numbers, kynurenine metabolites and lipid metabolites, which highlighted candidate immunologic and metabolic pathways influencing the restoration of homeostasis, the risk of death and that of long COVID. Based on these data, we identified a composite signature predictive of systemic recovery, using a joint model on cellular and molecular parameters measured soon after disease onset. New predictions can be generated using the online tool http://shiny.mrc-bsu.cam.ac.uk/apps/covid-19-systemic-recovery-prediction-app , designed to test our findings prospectively.

PMID:36717723 | DOI:10.1038/s41590-022-01380-2

Diabetes is associated with increased burden of gastrointestinal symptoms in adults with cystic fibrosis

Sun, 29/01/2023 - 11:00

J Cyst Fibros. 2023 Jan 27:S1569-1993(23)00018-8. doi: 10.1016/j.jcf.2023.01.010. Online ahead of print.

ABSTRACT

BACKGROUND: Individuals with diabetes mellitus (DM) are known to frequently experience gastrointestinal (GI) symptoms. In contrast, the impact of cystic fibrosis-related diabetes (CFRD) on accentuating GI symptoms in people with cystic fibrosis (pwCF) is unknown. We sought to examine this.

METHODS: Abdominal symptoms were measured using the validated CF-specific GI symptom questionnaire - CFAbd-Score© - as part of a multicentre cohort study in pancreatic insufficient adults with CF, not on cystic fibrosis transmembrane conductance regulator (CFTR) modulators. The CFAbd-Score total score (0-100pts), its 5 domains, alongside nine specific GI symptoms associated with DM, were compared between the CFRD and non-CFRD groups.

RESULTS: 27 (31%) and 61 (69%) participants with CF were recruited in the CFRD and non-CFRD groups respectively. Total CFAbd-Score and the two domains: gastroesophageal reflux disease and disorders of appetite were significantly higher in the CFRD group compared to the non-CFRD group (p<0.05), with the mean total CFAbd-Score being 25.4 ± 2.5 and 18.4 ± 1.5 in the CFRD and non-CFRD groups respectively. Among the nine GI symptoms commonly reported as elevated in DM, bloating and nausea were significantly more common in individuals with CFRD compared to those without (p<0.05).

CONCLUSIONS: Individuals with CFRD overall, have a higher GI symptom burden, according to CFAbd-Scores. Specifically, they experience significantly more bloating and nausea. Close monitoring and further research is needed to better understand and manage GI symptoms in this group.

PMID:36710099 | DOI:10.1016/j.jcf.2023.01.010

Multi-omics data integration methods and their applications in psychiatric disorders

Fri, 27/01/2023 - 11:00

Eur Neuropsychopharmacol. 2023 Jan 25;69:26-46. doi: 10.1016/j.euroneuro.2023.01.001. Online ahead of print.

ABSTRACT

To study mental illness and health, in the past researchers have often broken down their complexity into individual subsystems (e.g., genomics, transcriptomics, proteomics, clinical data) and explored the components independently. Technological advancements and decreasing costs of high throughput sequencing has led to an unprecedented increase in data generation. Furthermore, over the years it has become increasingly clear that these subsystems do not act in isolation but instead interact with each other to drive mental illness and health. Consequently, individual subsystems are now analysed jointly to promote a holistic understanding of the underlying biological complexity of health and disease. Complementing the increasing data availability, current research is geared towards developing novel methods that can efficiently combine the information rich multi-omics data to discover biologically meaningful biomarkers for diagnosis, treatment, and prognosis. However, clinical translation of the research is still challenging. In this review, we summarise conventional and state-of-the-art statistical and machine learning approaches for discovery of biomarker, diagnosis, as well as outcome and treatment response prediction through integrating multi-omics and clinical data. In addition, we describe the role of biological model systems and in silico multi-omics model designs in clinical translation of psychiatric research from bench to bedside. Finally, we discuss the current challenges and explore the application of multi-omics integration in future psychiatric research. The review provides a structured overview and latest updates in the field of multi-omics in psychiatry.

PMID:36706689 | DOI:10.1016/j.euroneuro.2023.01.001

Questioning the fetal microbiome illustrates pitfalls of low-biomass microbial studies

Wed, 25/01/2023 - 11:00

Nature. 2023 Jan;613(7945):639-649. doi: 10.1038/s41586-022-05546-8. Epub 2023 Jan 25.

ABSTRACT

Whether the human fetus and the prenatal intrauterine environment (amniotic fluid and placenta) are stably colonized by microbial communities in a healthy pregnancy remains a subject of debate. Here we evaluate recent studies that characterized microbial populations in human fetuses from the perspectives of reproductive biology, microbial ecology, bioinformatics, immunology, clinical microbiology and gnotobiology, and assess possible mechanisms by which the fetus might interact with microorganisms. Our analysis indicates that the detected microbial signals are likely the result of contamination during the clinical procedures to obtain fetal samples or during DNA extraction and DNA sequencing. Furthermore, the existence of live and replicating microbial populations in healthy fetal tissues is not compatible with fundamental concepts of immunology, clinical microbiology and the derivation of germ-free mammals. These conclusions are important to our understanding of human immune development and illustrate common pitfalls in the microbial analyses of many other low-biomass environments. The pursuit of a fetal microbiome serves as a cautionary example of the challenges of sequence-based microbiome studies when biomass is low or absent, and emphasizes the need for a trans-disciplinary approach that goes beyond contamination controls by also incorporating biological, ecological and mechanistic concepts.

PMID:36697862 | DOI:10.1038/s41586-022-05546-8

Deletion of the Transcriptional Coactivator HCF-1 <em>In Vivo</em> Impairs the Removal of Repressive Heterochromatin from Latent HSV Genomes and Suppresses the Initiation of Viral Reactivation

Tue, 24/01/2023 - 11:00

mBio. 2023 Jan 24:e0354222. doi: 10.1128/mbio.03542-22. Online ahead of print.

ABSTRACT

Transcription of herpes simplex virus 1 (HSV-1) immediate early (IE) genes is controlled at multiple levels by the cellular transcriptional coactivator, HCF-1. HCF-1 is complexed with epigenetic factors that prevent silencing of the viral genome upon infection, transcription factors that drive initiation of IE gene expression, and transcription elongation factors required to circumvent RNAPII pausing at IE genes and promote productive IE mRNA synthesis. Significantly, the coactivator is also implicated in the control of viral reactivation from latency in sensory neurons based on studies that demonstrate that HCF-1-associated epigenetic and transcriptional elongation complexes are critical to initiate IE expression and viral reactivation. Here, an HCF-1 conditional knockout mouse model (HCF-1cKO) was derived to probe the role and significance of HCF-1 in the regulation of HSV-1 latency/reactivation in vivo. Upon deletion of HCF-1 in sensory neurons, there is a striking reduction in the number of latently infected neurons that initiate viral reactivation. Importantly, this correlated with a defect in the removal of repressive chromatin associated with latent viral genomes. These data demonstrate that HCF-1 is a critical regulatory factor that governs the initiation of HSV reactivation, in part, by promoting the transition of latent viral genomes from a repressed heterochromatic state. IMPORTANCE Herpes simplex virus is responsible for a substantial worldwide disease burden. An initial infection leads to the establishment of a lifelong persistent infection in sensory neurons. Periodic reactivation can result in recurrent oral and genital lesions to more significant ocular disease. Despite the significance of this pathogen, many of the regulatory factors and molecular mechanisms that govern the viral latency-reactivation cycles have yet to be elucidated. Initiation of both lytic infection and reactivation are dependent on the expression of the viral immediate early genes. In vivo deletion of a central component of the IE regulatory paradigm, the cellular transcriptional coactivator HCF-1, reduces the epigenetic transition of latent viral genomes, thus suppressing HSV reactivation. These observations define HCF-1 as a critical regulator that controls the initiation of HSV reactivation from latency in vivo and contribute to understanding of the molecular mechanisms that govern viral reactivation.

PMID:36692302 | DOI:10.1128/mbio.03542-22

Development and validation of a dynamic 48-hour in-hospital mortality risk stratification for COVID-19 in a UK teaching hospital: a retrospective cohort study

Mon, 23/01/2023 - 11:00

BMJ Open. 2022 Sep 5;12(9):e060026. doi: 10.1136/bmjopen-2021-060026.

ABSTRACT

OBJECTIVES: To develop a disease stratification model for COVID-19 that updates according to changes in a patient's condition while in hospital to facilitate patient management and resource allocation.

DESIGN: In this retrospective cohort study, we adopted a landmarking approach to dynamic prediction of all-cause in-hospital mortality over the next 48 hours. We accounted for informative predictor missingness and selected predictors using penalised regression.

SETTING: All data used in this study were obtained from a single UK teaching hospital.

PARTICIPANTS: We developed the model using 473 consecutive patients with COVID-19 presenting to a UK hospital between 1 March 2020 and 12 September 2020; and temporally validated using data on 1119 patients presenting between 13 September 2020 and 17 March 2021.

PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome is all-cause in-hospital mortality within 48 hours of the prediction time. We accounted for the competing risks of discharge from hospital alive and transfer to a tertiary intensive care unit for extracorporeal membrane oxygenation.

RESULTS: Our final model includes age, Clinical Frailty Scale score, heart rate, respiratory rate, oxygen saturation/fractional inspired oxygen ratio, white cell count, presence of acidosis (pH <7.35) and interleukin-6. Internal validation achieved an area under the receiver operating characteristic (AUROC) of 0.90 (95% CI 0.87 to 0.93) and temporal validation gave an AUROC of 0.86 (95% CI 0.83 to 0.88).

CONCLUSIONS: Our model incorporates both static risk factors (eg, age) and evolving clinical and laboratory data, to provide a dynamic risk prediction model that adapts to both sudden and gradual changes in an individual patient's clinical condition. On successful external validation, the model has the potential to be a powerful clinical risk assessment tool.

TRIAL REGISTRATION: The study is registered as 'researchregistry5464' on the Research Registry (www.researchregistry.com).

PMID:36691139 | DOI:10.1136/bmjopen-2021-060026

Air pollution and anti-social behaviour: Evidence from a randomised lab-in-the-field experiment

Sat, 21/01/2023 - 11:00

Soc Sci Med. 2022 Dec 28;320:115617. doi: 10.1016/j.socscimed.2022.115617. Online ahead of print.

ABSTRACT

We conducted a pre-registered randomised lab-in-the-field online experiment in Beijing, China, to explore the relationship between acute air pollution and anti-social behaviour. Our novel experimental design exploits naturally occurring discontinuities in pollution episodes to mimic an experimental setting in which pollution exposure is exogenously manipulated, thus allowing us to identify a causal relationship. Participants were randomly assigned to be surveyed on either high pollution or low pollution days, thereby exogenously varying the degree of pollution exposure. In addition, a subset of individuals surveyed on the high-pollution days received an additional 'pollution alert' to explore whether providing air pollution warnings influences (protective) behaviour. We used a set of well-established incentivised economic games to obtain clean measures of anti-social behaviour, as well as a range of secondary outcomes which may drive the proposed pollution-behaviour relationship. Our results indicate that exposure to acute air pollution had no statistically significant effect on anti-social behaviour, but significantly reduced both psychological and physiological well-being. However, these effects do not remain statistically significant after adjusting for multiple hypothesis testing. We find no evidence that pollution affects cognitive ability, present bias, discounting, or risk aversion, four potential pathways which may explain the relationship between pollution and anti-social behaviour. Our study adds to the growing calls for purposefully designed and pre-registered experiments that strengthen experimental (as opposed to correlational or quasi-experimental) identification and thus allow causal insights into the relationship between pollution and anti-social behaviour.

PMID:36681056 | DOI:10.1016/j.socscimed.2022.115617

Antigenic mapping of emerging SARS-CoV-2 omicron variants BM.1.1.1, BQ.1.1, and XBB.1

Thu, 19/01/2023 - 11:00

Lancet Microbe. 2023 Jan 16:S2666-5247(22)00384-6. doi: 10.1016/S2666-5247(22)00384-6. Online ahead of print.

NO ABSTRACT

PMID:36657480 | DOI:10.1016/S2666-5247(22)00384-6