Structural and functional characterization of nanobodies that neutralize Omicron variants of SARS-CoV-2.

The Omicron strains of SARS-CoV-2 pose a significant challenge to the development of effective antibody-based treatments as immune evasion has compromised most available immune therapeutics. Therefore, in the 'arms race' with the virus, there is a continuing need to identify new biologics for the prevention or treatment of SARS-CoV-2 infections. Here, we report the isolation of nanobodies that bind to the Omicron BA.

Safety, tolerability, viral kinetics, and immune correlates of protection in healthy, seropositive UK adults inoculated with SARS-CoV-2: a single-centre, open-label, phase 1 controlled human infection study.

Background: A SARS-CoV-2 controlled human infection model (CHIM) has been successfully established in seronegative individuals using a dose of 1×10 50% tissue culture infectious dose (TCID) pre-alpha SARS-CoV-2 virus. Given the increasing prevalence of seropositivity to SARS-CoV-2, a CHIM that could be used for vaccine development will need to induce infection in those with pre-existing immunity. Our aim was to find a dose of pre-alpha SARS-CoV-2 virus that induced infection in previously infected individuals.

Obesity differs from diabetes mellitus in antibody and T-cell responses post-COVID-19 recovery.

Objective: Obesity and type 2 diabetes (DM) are risk factors for severe coronavirus disease 2019 (COVID-19) outcomes, which disproportionately affect South Asian populations. This study aims to investigate the humoral and cellular immune responses to SARS-CoV-2 in adult COVID-19 survivors with overweight/obesity (Ov/Ob, BMI ≥ 23 kg/m2) and DM in Bangladesh.

Methods: In this cross-sectional study, SARS-CoV-2-specific antibody and T-cell responses were investigated in 63 healthy and 75 PCR-confirmed COVID-19 recovered individuals in Bangladesh, during the pre-vaccination first wave of the COVID-19 pandemic in 2020.

SARS-CoV-2-specific immune responses and clinical outcomes after COVID-19 vaccination in patients with immune-suppressive disease.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immune responses and infection outcomes were evaluated in 2,686 patients with varying immune-suppressive disease states after administration of two Coronavirus Disease 2019 (COVID-19) vaccines. Overall, 255 of 2,204 (12%) patients failed to develop anti-spike antibodies, with an additional 600 of 2,204 (27%) patients generating low levels (<380 AU ml). Vaccine failure rates were highest in ANCA-associated vasculitis on rituximab (21/29, 72%), hemodialysis on immunosuppressive therapy (6/30, 20%) and solid organ transplant recipients (20/81, 25% and 141/458, 31%).

Mapping single-cell transcriptomes in the intra-tumoral and associated territories of kidney cancer.

Tumor behavior is intricately dependent on the oncogenic properties of cancer cells and their multi-cellular interactions. To understand these dependencies within the wider microenvironment, we studied over 270,000 single-cell transcriptomes and 100 microdissected whole exomes from 12 patients with kidney tumors, prior to validation using spatial transcriptomics. Tissues were sampled from multiple regions of the tumor core, the tumor-normal interface, normal surrounding tissues, and peripheral blood.

Convalescent plasma donors show enhanced cross-reactive neutralizing antibody response to antigenic variants of SARS-CoV-2 following immunization.

Background: The therapeutic benefit of convalescent plasma (CP) therapy to treat COVID-19 may derive from neutralizing antibodies (nAbs) to SARS-CoV-2. To investigate the effects of antigenic variation on neutralization potency of CP, we compared nAb titers against prototype and recently emerging strains of SARS-CoV-2, including Delta and Omicron, in CP donors previously infected with SARS-CoV-2 before and after immunization.

Methods And Materials: Samples were assayed from previously SARS-CoV-2 infected donors before (n = 17) and after one (n = 43) or two (n = 71) doses of Astra-Zeneca or Pfizer vaccinations.

Integrating lived experiences of out-of-hours health services for people with palliative and end-of-life care needs with national datasets for people dying in Scotland in 2016: A mixed methods, multi-stage design.

Background: Unscheduled care is used increasingly during the last year of life by people known to have significant palliative care needs.

Aim: To document the frequency and patterns of use of unscheduled healthcare by people in their last year of life and understand the experiences and perspectives of patients, families and professionals about accessing unscheduled care out-of-hours.

Design: A mixed methods, multi-stage study integrating a retrospective cohort analysis of unscheduled healthcare service use in the last year of life for all people dying in Scotland in 2016 with qualitative data from three regions involving service users, bereaved carers and general practitioners.

TRIM21/Ro52 - Roles in Innate Immunity and Autoimmune Disease.

TRIM21 (Ro52/SSA1) is an E3 ubiquitin ligase with key roles in immune host defence, signal transduction, and possibly cell cycle regulation. It is also an autoantibody target in Sjögren's syndrome, systemic lupus erythematosus, and other rheumatic autoimmune diseases. Here, we summarise the structure and function of this enzyme, its roles in innate immunity, adaptive immunity and cellular homeostasis, the pathogenesis of autoimmunity against TRIM21, and the potential impacts of autoantibodies to this intracellular protein.

Common clonal origin of conventional T cells and induced regulatory T cells in breast cancer patients.

Regulatory CD4 T cells (Treg) prevent tumor clearance by conventional T cells (Tconv) comprising a major obstacle of cancer immune-surveillance. Hitherto, the mechanisms of Treg repertoire formation in human cancers remain largely unclear. Here, we analyze Treg clonal origin in breast cancer patients using T-Cell Receptor and single-cell transcriptome sequencing.

Modulation of Early Host Innate Immune Response by an Avipox Vaccine Virus' Lateral Body Protein.

The avian pathogen fowlpox virus (FWPV) has been successfully used as a vaccine vector in poultry and humans, but relatively little is known about its ability to modulate host antiviral immune responses in these hosts, which are replication-permissive and nonpermissive, respectively. FWPV is highly resistant to avian type I interferon (IFN) and able to completely block the host IFN-response. Microarray screening of host IFN-regulated gene expression in cells infected with 59 different, nonessential FWPV gene knockout mutants revealed that FPV184 confers immunomodulatory capacity.

Tumor Necrosis Factor Inhibits Spread of Hepatitis C Virus Among Liver Cells, Independent From Interferons.

Background & Aims: Tumor necrosis factor (TNF) is an inflammatory cytokine expressed by human fetal liver cells (HFLCs) after infection with cell culture-derived hepatitis C virus (HCV). TNF has been reported to increase entry of HCV pseudoparticles into hepatoma cells and inhibit signaling by interferon alpha (IFNα), but have no effect on HCV-RNA replication. We investigated the effects of TNF on HCV infection of and spread among Huh-7 hepatoma cells and primary HFLCs.

MAIT cells are activated during human viral infections.

Mucosal-associated invariant T (MAIT) cells are abundant in humans and recognize bacterial ligands. Here, we demonstrate that MAIT cells are also activated during human viral infections in vivo. MAIT cells activation was observed during infection with dengue virus, hepatitis C virus and influenza virus.

Interferon lambda: opportunities, risks, and uncertainties in the fight against HCV.

Innate immunity is key to the fight against the daily onslaught from viruses that our bodies are subjected to. Essential to this response are the interferons (IFNs) that prime our cells to block viral pathogens. Recent evidence suggests that the Type III (λ) IFNs are intimately associated with the immune response to hepatitis C virus (HCV) infection.

Immune control and failure in HCV infection--tipping the balance.

Despite the development of potent antiviral drugs, HCV remains a global health problem; global eradication is a long way off. In this review, we discuss the immune response to HCV infection and particularly, the interplay between viral strategies that delay the onset of antiviral responses and host strategies that limit or even eradicate infected cells but also contribute to pathogenesis. Although HCV can disable some cellular virus-sensing machinery, IFN-stimulated antiviral genes are induced in the infected liver.

Construction of Deletion-knockout Mutant Fowlpox Virus (FWPV).

The construction of deletion-knockout poxviruses is a useful approach to determining the function of specific virus genes. This protocol is an adaptation of the transient dominant knockout selection protocol published by Falkner and Moss (1990) for use with vaccinia virus. The protocol makes use of the dominant selectable marker guanine phosphoribosyltransferase (gpt) gene (Mulligan and Berg, 1981), under the control of an early/late poxvirus promoter.

Genetic screen of a mutant poxvirus library identifies an ankyrin repeat protein involved in blocking induction of avian type I interferon.

Mammalian poxviruses, including vaccinia virus (VACV), have evolved multiple mechanisms to evade the host type I interferon (IFN) responses at different levels, with viral proteins targeting IFN induction, signaling, and antiviral effector functions. Avian poxviruses (avipoxviruses), which have been developed as recombinant vaccine vectors for permissive (i.e.

Genetic screen of a library of chimeric poxviruses identifies an ankyrin repeat protein involved in resistance to the avian type I interferon response.

Viruses must be able to resist host innate responses, especially the type I interferon (IFN) response. They do so by preventing the induction or activity of IFN and/or by resisting the antiviral effectors that it induces. Poxviruses are no exception, with many mechanisms identified whereby mammalian poxviruses, notably, vaccinia virus (VACV), but also cowpox and myxoma viruses, are able to evade host IFN responses.

Real world usage of PCC to "rapidly" correct warfarin induced coagulopathy.

Background: Life threatening bleeding and emergency procedures in patients on vitamin K antagonists are indications for urgent reversal with prothrombin complex concentrate and vitamin K. Rapid reversal in these situations is emphasized in the literature and guidelines, but only very limited information is available on its real life use, especially on the timing of treatment in relation to presentation.

Materials And Methods: We retrospectively audited emergency warfarin reversal in 131 consecutive patients.

Protamine reversal of low molecular weight heparin: clinically effective?

Low molecular weight heparins (LMWHs) are frequently used in the prophylaxis or treatment of venous thrombosis, acute coronary syndromes and peri-operative bridging. Major bleeding occurs in 1-4% depending on dose and underlying condition. Protamine is recommended for reversal but only partially reverses the anti-Xa activity and there are very limited data on clinical effectiveness.