Department of Biomedicine Basel

A deeper understanding of how tissue-localized immune cells arise and function is critical for developing mucosal vaccines. Currently, there are no murine models that specifically target tissue T cells while leaving their lymphoid counterparts untouched. Here, we leverage the observation that during influenza infection, HIF-1α regulatory activity is higher in the lung compared with lymph node CD4+ T cells. Inducible deletion of Hif1a in CD4+ T cells, at the onset of its activity in the lung, reduces the tissue-resident T cell compartment with minimal impact on peripheral immunity. HIF-1α-active CD4+ T cells occupy the border of tertiary lymphoid structures, where they coordinate an interleukin 21 (IL-21)-dependent network of spatially colocalized immune cells including macrophages, natural killer (NK) cells, and immunoglobulin A-positive (IgA+) B cells. A similar HIF-1α-dependent network is engaged in a lung adenocarcinoma model, highlighting a broader role for HIF-1α+ CD4+ T cells in integrating protective immunity during infection and cancer.

Coronaviruses (family Coronaviridae, order Nidovirales) include major human and animal pathogens. They have exceptionally large RNA genomes and use complex strategies to replicate and express these genomes. Intensive research activities in recent years have significantly advanced our knowledge of the molecular mechanisms involved in coronavirus RNA synthesis. Here, we briefly review these mechanisms and focus in particular on the structures and functions of the core replication-transcription complex (RTC) and other enzyme functions that can be recruited to this complex to fulfil additional functions, for example, in the context of 5' capping of viral mRNAs or in the context of mechanisms that control the processivity, replication fidelity, and backtracking of RTCs. Some of these recent studies provided fundamentally new insight into specific roles of previously identified genetic markers of coronaviruses and other nidoviruses, including specific functions in an unconventional RNA capping mechanism and potential roles in proofreading and discontinuous negative-strand RNA synthesis.

Mitochondria are organelles with a hypomethylated circular genome. Mitochondrial DNA (mtDNA) in the systemic circulation has been implicated in inflammation. This study investigates the role of circulating DNA in systemic sclerosis (SSc) and the cellular mechanisms governing its release. Total DNA was isolated from the plasma of healthy controls (HCs) and patients with SSc. Copy numbers were analyzed for mtDNA (ATP-6) and GAPDH abundance by quantitative real-time polymerase chain reaction. mtDNA was isolated from HCs and patients with SSc. Neutrophils and platelets were incubated with the plasma and mtDNA of patients with SSc, and neutrophil extracellular trap (NET) formation was assessed by SytoxGreen and immunostainings. Platelets were tested for mtDNA release propensity. DNA oxidation was evaluated by MitoSOX Red staining in vitro and 8-OHdG enzyme-linked immunosorbent assay (ELISA) of patient plasma. Plasma interferon (IFN) type 1 and chemokine (C-X-C motif) ligand 4 (CXCL4) were measured by ELISA. IFN signaling activation capacity was evaluated using THP-1 reporter cells and confirmed by a whole blood bulk RNA transcriptomic analysis. Median plasma mtDNA levels were 152-fold higher in patients with SSc compared with HCs, whereas nuclear DNA levels were similar. mtDNA from SSc plasma was highly oxidized. SSc-derived mtDNA efficiently promoted its own release by NETosis, most potently in the neutrophils of patients with SSc and by platelet activation. Oxidized mtDNA from SSc platelets in complex with CXCL4 further stimulated mtDNA release in both neutrophils and platelets. mtDNA plasma concentrations correlated with type I IFN concentrations in the blood of patients with SSc, and SSc blood exhibited elevated IFN-stimulated gene expression. SSc plasma-derived mtDNA-induced IFN signaling and NET formation via endosomal Toll-like receptors, cyclic GMP-AMP synthase/stimulator of IFN genes, and the JAK/STAT pathway. The type I IFN pathway further promoted NETosis and mtDNA release because IFN receptor and JAK inhibition antagonized the proNETotic effects of IFN. SSc plasma is characterized by highly abundant mtDNA, which drives feedback loops amplifying its own release from both neutrophils and platelets. Thus, mtDNA contributes to inflammation and tissue damage in SSc.

Healthcare across Europe was affected by COVID-19 pandemic lockdowns. How different national healthcare systems coped with this impact remains unclear. Healthcare in Switzerland differs significantly from that in Scotland, for example, in terms of centralization. The aim of this study was to assess the impact of the COVID-19 pandemic on the diagnosis and surgical treatment of colorectal cancer (CRC) in contrasting healthcare systems. This retrospective cohort study was conducted in south-east Scotland and in the extended north-west of Switzerland from January 1st, 2019 to February 28th, 2023. All patients diagnosed with CRC were included. The primary outcomes were the time from CRC diagnosis to treatment and the UICC stage at diagnosis, assessed prior to, during, and following the period of lockdown. The lockdown in Scotland lasted from March 2020 to October 2020 and in Switzerland from March 2020 to April 2020. A total of 6745 patients were included (4127 from Scotland and 2618 from Switzerland). Median time from diagnosis to treatment remained unaltered during the lockdown period in both countries. However, after the lockdown, the median time from diagnosis to treatment increased from 59 to 76days in Scotland. The median number of patients who were diagnosed per annual quarter declined from 177 (IQR: 171-190) to 152 (IQR: 150-154), and the median number of who received treatment from declined from 256 (IQR: 253-259) to 203 (IQR: 186-218) during lockdown in Scotland. In multivariable logistic regression, the odds of being diagnosed with UICC stage IV increased by 42% for patients diagnosed during lockdown (95%-CI: 12%-81%). In Switzerland, the time from diagnosis to treatment increased slightly after the pandemic. However, the other effects described above were not observed in Switzerland. This descriptive study demonstrated that the impact of the pandemic on colorectal cancer care was less pronounced in Switzerland, but considerable in Scotland. Because separate subgroup analyses were conducted, direct comparisons cannot be made between Scotland and Switzerland. This trial is registered on clinicaltrials.gov as part of the EvaCol study (NCT04550156).

Loneliness is associated with adverse physical and mental health outcomes. It affects individuals across all age groups and geographical regions. To characterise the extent that WHO Member States address loneliness, social isolation and social connection through national policies. We searched government websites using key terms. A matrix was used to extract data, followed by in-depth document analysis. By February 2025, only eight WHO Member States (Denmark, UK (England, Scotland, Wales), Finland, Germany, Netherlands, Sweden, Japan, USA) had policies directly addressing loneliness, social isolation or social connection. Policymakers validated the findings. Common policy aims included building a more connected society, addressing loneliness as a wider societal challenge rather than just an individual issue, and supporting both individuals and organisations to manage loneliness. Key recommendations in these policies often highlighted the need to increase knowledge through research, raise public awareness to reduce stigma, promote cross-sectoral collaboration, integrate loneliness into government policy and implement community-based approaches. National policies emerged following societal activism, initiatives from government departments or a large-scale research project. Various policies are in place to help address loneliness at the national level. To maximise impact, policies require adequate funding. To date, none of the national policies had undergone rigorous evaluation concerning their effectiveness. This review highlights the growing political focus on loneliness and provides a starting point for those seeking to understand, develop or strengthen national strategies to address loneliness, social isolation or social connection.

Objectives To define stromal-immune cell crosstalk in cutaneous lupus erythematosus (CLE) using a data-driven approach.Methods We performed 3' scRNA-seq on lesional and non-lesional skin biopsies from patients with subacute cutaneous lupus (SCLE) and healthy volunteers (HV).Cell-cell communication was interrogated by combining LIANA+ consensus analysis with tensor-cell2cell (dimensionality reduction).We interpreted biological information from interactions using gene set enrichment (Reactome) and functional enrichment (PROGENy). ResultsWe analysed fibroblasts (FBs), monocytes, NK, and T cells from paired lesional and non-lesional samples from 3 patients and samples from 3 HV.We identified 8 cell-cell context aware factors, each representing a cell-cell communication

Single-cell epigenome and transcriptome profiling enables the dissection of gene regulatory networks, offering a powerful approach to characterize cellular heterogeneity and regulatory landscapes of cell states. Here we describe a single-cell ultra-high-throughput multiplexed sequencing (SUM-seq) assay for scalable and cost-effective simultaneous profiling of chromatin accessibility and gene expression in single nuclei. SUM-seq combines sample-specific accessible DNA and mRNA in situ barcoding with droplet-based microfluidic barcoding, introducing sample multiplexing and means to resolve multinucleated droplets for multiomic single-cell library preparation. In comparison with existing methods for multimodal profiling of chromatin accessibility and gene expression from the same cell, SUM-seq offers increased throughput and an unmatched multiplexing capability. This permits substantial scaling of the number of samples and nuclei assayed in one experiment, adhering to the needs of large-scale atlas projects, time-course experiments and perturbation screens while considerably reducing costs. We provide guidelines for experimental design and sample handling to accommodate various settings and sample types. Moreover, we discuss potential applications and provide guidelines for data processing. From sample collection to library preparation, the assay can be completed in 2-3 days, followed by sequencing and 1 day of data processing. Although the protocol can be implemented by researchers with general molecular biology skills, prior experience with single-cell assays is recommended.

The COVID-19 pandemic significantly impacted the mental health of the Swiss population. This study analyzed data from the Collaborative Outcome study on Health and Functioning during Infection Times (COH-FIT) across three pandemic waves: T1 (April-June 2020), T2 (July-December 2020) or T3 (January-June 2021). Each participant participated only once, during one of these three waves. Participants reported their subjective well-being and mental health status for the two weeks prior to the pandemic (pre-pandemic baseline) and during their respective pandemic wave. Subjective well-being was assessed using the World Health Organization Well-Being Index (WHO-5) from 4,037 participants, while mental health was measured via the P-score, completed by 3,375 participants. The WHO-5 ranges from 0 to 100, with higher scores indicating better well-being, while the P-score also ranges from 0 to 100 whereas higher scores represent greater levels of perceived burden across five domains of mental health. Pre- and intra-pandemic differences were analyzed using Wilcoxon tests and ANOVA, with subgroup analyses across seven Swiss regions utilizing the Kruskal-Wallis test. Participants had a mean age of 45.6 years (61.9% female). Results showed a substantial decline in well-being during the pandemic, with average WHO-5 scores decreasing from 75.3 pre-pandemic, to 66.5 during the first wave, 69.1 during the second, and 65.1 during the third, representing relative reductions of 11.7%, 8.2%, and 13.5%. The percentage of participants at risk for depression (WHO-5 <50) peaked during the third wave at 19.8%, up from 10.0% pre-pandemic. Mental health burden, as measured by the P-score, increased significantly during the first wave (from 20.6 to 27.3, +32.5%), and remained elevated across the two subsequent waves, with no significant recovery observed. Wilcoxon tests indicated significant differences between pre-pandemic and intra-pandemic WHO-5 and P-scores, with the largest effect sizes during the third wave (r = 0.652 for WHO-5; r = 0.487 for P-score). ANOVA showed significant intra-pandemic differences in WHO-5 across waves (p < 0.001), with improvements noted in the second wave. However, no intra-pandemic differences in P-scores were found (p = 0.298). Regional analyses revealed that Ticino, the Lake Geneva region, and Northwestern Switzerland experienced the most pronounced declines in well-being and increases in mental health burden. In contrast, Espace Mittelland and Eastern Switzerland experienced a less severe impact. Overall, these findings highlight the considerable and lasting impact of COVID-19 on mental health in Switzerland, emphasizing the need for targeted interventions, particularly in the most affected regions.

Subchondral bone (SCB) remodels in response to long-term mechanical loading, with mineralisation patterns reflecting chronic mechanical stress. Computed tomography osteoabsorptiometry (CT-OAM) enables non-invasive visualisation of these adaptations. While CT-OAM has been widely applied to several joints, its use in the pubic symphysis is limited. This study aimed to identify sex- and age-related differences in mineralisation patterns and quantify bone mineral density (BMD) distribution across the symphyseal surfaces. CT scans from 85 individuals (51 males, 34 females; age range 18–97 years) were analysed, generating 170 symphyseal surfaces. Segmented three-dimensional reconstructions were processed into HU-based densitograms. Mineralisation was classified qualitatively into three patterns: diffuse across the surface (Pattern 1), ventral border with/without inferior apex involvement (Pattern 2), and dorsal border with/without inferior apex involvement (Pattern 3). Quantitatively, each surface was subdivided into six anatomical subregions, and mean HU values were compared by sex, side, and age. Across all specimens, Pattern 2 predominated (58%), with Pattern 2 most frequent in males (76%) and Pattern 3 in females (55%). High bilateral conformity (81%) was observed. Males exhibited significantly higher mean HU values than females (554 ± 180 HU vs. 374 ± 111 HU, p < 0.01), with greater BMD across all subregions. Region-specific analyses revealed highest mineralisation anteriorly and inferiorly in males, while females displayed increased posterior mineralisation. No significant correlation was found between overall BMD and age; however, females demonstrated a weak negative correlation in the ventral middle region (r = − 0.24, p < 0.05). This study provides the first systematic CT-OAM analysis of pubic symphyseal SCB mineralisation. Findings highlight sex-specific patterns, with males demonstrating greater anterior and inferior mineralisation, and females exhibiting posterior dominance. Males also displayed higher overall BMD, reflecting greater chronic loading. These results deepen understanding of pelvic biomechanics and may inform future research on conditions such as osteitis pubis.