Single-cell transcriptomic analysis of antiviral responses and viral antagonism in Chikungunya virus-infected synovial fibroblasts

In recent years, (re-)emerging arboviruses including Chikungunya virus (CHIKV) and Mayaro virus (MAYV) have caused growing concern due to expansion of insect vector ranges. No protective vaccine or specific antiviral strategies are currently available. Long-term morbidity after CHIKV infection includes debilitating chronic joint pain, which has associated health and economic impact. Here, we analyzed the early cell-intrinsic response to CHIKV and MAYV infection in primary human synovial fibroblasts. This interferon-competent cell type represents a potential source of polyarthralgia induced by CHIKV infection. Synovial fibroblasts from healthy and osteoarthritic donors were similarly permissive to CHIKV and MAYV infection ex vivo. Using RNA-seq, we defined a CHIKV infection-induced transcriptional profile with several hundred interferon-stimulated and arthralgia-mediating genes upregulated. Type I interferon was both secreted by infected fibroblasts and protective when administered exogenously. IL-6 secretion, which mediates chronic synovitis, however, was not boosted by infection. Single-cell RNA-seq and flow cytometric analyses uncovered an inverse correlation of activation of innate immunity and productive infection at the level of individual cells. In summary, primary human synovial fibroblasts serve as bona-fide ex vivo primary cell model of CHIKV infection and provide a valuable platform for studies of joint tissue-associated aspects of CHIKV immunopathogenesis

Non-linear response of a Kondo system: Perturbation approach to the time dependent Anderson impurity model

Nonlinear tunneling current through a quantum dot (an Anderson impurity system) subject to both constant and alternating electric fields is studied in the Kondo regime. A systematic diagram technique is developed for perturbation study of the current in physical systems out of equilibrium governed by time - dependent Hamiltonians of the Anderson and the Kondo models. The ensuing calculations prove to be too complicated for the Anderson model, and hence, a mapping on an effective Kondo problem is called for. This is achieved by constructing a time - dependent version of the Schrieffer - Wolff transformation. Perturbation expansion of the current is then carried out up to third order in the Kondo coupling J yielding a set of remarkably simple analytical expressions for the current. The zero - bias anomaly of the direct current differential conductance is shown to be suppressed by the alternating field while side peaks develop at finite source - drain voltage. Both the direct component and the first harmonics of the time - dependent response are equally enhanced due to the Kondo effect, while amplitudes of higher harmonics are shown to be relatively small. A zero alternating bias anomaly is found in the alternating current differential conductance, that is, it peaks around zero alternating bias. This peak is suppressed by the constant bias. No side peaks show up in the differential alternating - conductance but their counterpart is found in the derivative of the alternating current with respect to the direct bias. The results pertaining to nonlinear response are shown to be valid also below the Kondo temperature.Comment: 55 latex pages 11 ps figure

Vaccine-associated enhanced respiratory pathology in COVID-19 hamsters after T(H)2-biased immunization

Vaccine-associated enhanced respiratory disease (VAERD) is a severe complication for some respiratory infections. To investigate the potential for VAERD induction in coronavirus disease 2019 (COVID-19), we evaluate two vaccine leads utilizing a severe hamster infection model: a T helper type 1 (T(H)1)-biased measles vaccine-derived candidate and a T(H)2-biased alum-adjuvanted, non-stabilized spike protein. The measles virus (MeV)-derived vaccine protects the animals, but the protein lead induces VAERD, which can be alleviated by dexamethasone treatment. Bulk transcriptomic analysis reveals that our protein vaccine prepares enhanced host gene dysregulation in the lung, exclusively up-regulating mRNAs encoding the eosinophil attractant CCL-11, T(H)2-driving interleukin (IL)-19, or T(H)2 cytokines IL-4, IL-5, and IL-13. Single-cell RNA sequencing (scRNA-seq) identifies lung macrophages or lymphoid cells as sources, respectively. Our findings imply that VAERD is caused by the concerted action of hyperstimulated macrophages and T(H)2 cytokine-secreting lymphoid cells and potentially links VAERD to antibody-dependent enhancement (ADE). In summary, we identify the cytokine drivers and cellular contributors that mediate VAERD after T(H)2-biased vaccination

Using Talking Mats to support conversations with communication vulnerable people: A scoping review

BACKGROUND:Talking Mats™ is a framework developed to support communication with communication vulnerable people. OBJECTIVE: The objective was twofold: to provide an overview of the objectives, target groups and settings for which Talking Mats has been used (Part 1), and an overview of empirical scientific knowledge on the use of Talking Mats (Part 2). METHODS: In this scoping review scientific and grey literature was searched in PubMed, Cinahl, Psycinfo, Google, and Google Scholar. Articles that described characteristics of Talking Mats or its use were included. For Part 2, additional selection criteria were applied to focus on empirical scientific knowledge. RESULTS: The search yielded 73 publications in Part 1, 12 of which were included in Part 2. Talking Mats was used for functional objectives (e.g. goal setting) and to improve communication and involvement. Part 2 showed that Talking Mats had positive influences on technical communication, effectiveness of conversations, and involvement and decision making in conversations. However, the level of research evidence is limited. CONCLUSIONS:Talking Mats can be used to support conversations between professionals and communication vulnerable people. More research is needed to study the views of people who are communication vulnerable and to study the effects of Talking Mats