Cristina López

Abstract Metabolites, lipids, and other small molecules are key constituents of tissues supporting cellular programs in health and disease. Here, we present METASPACE, a community-populated knowledge base of spatial metabolomes from imaging mass spectrometry data. METASPACE is enabled by a high-performance engine for metabolite annotation in a confidence-controlled way that makes results comparable between experiments and laboratories. By sharing their results publicly, engine users continuously populate a knowledge base of annotated spatial metabolomes in tissues currently including over 3000 datasets from human cancer cohorts, whole-body sections of animal models, and various organs. The spatial metabolomes can be visualized, explored and shared using a web app as well as accessed programmatically for large-scale analysis. By using novel computational methods inspired by natural language processing, we illustrate that METASPACE provides molecular coverage beyond the capacity of any individual laboratory and opens avenues towards comprehensive metabolite atlases on the levels of tissues and organs.

The chromosomal translocation t(1;6)(p35.3;p25.2) is a rare but recurrent aberration in chronic lymphocytic leukaemia (CLL). We report molecular characterization of 10 cases and show that this translocation juxtaposes interferon regulatory factor 4 (IRF4) on 6p25 with regulator of chromosome condensation 1 (RCC1) on 1p35. The breakpoints fell within the 5' untranslated regions of both genes, resulting in RCC1::IRF4 fusion transcripts without alterations of the protein-coding sequences. Levels of expression of both RCC1 and IRF4 proteins were not obviously deregulated. The cases showed other mutations typical of CLL and we confirm previously reported skewing towards the IGHV-unmutated subtype. RCC1::IRF4 fusion characterizes a rare subset of CLL.

B-cell responses towards seasonal human coronaviruses (sHCoVs), particularly OC43, impacted those towards SARS-CoV-2 due to immune imprinting in severe COVID-19 patients. However, little is known on how widespread SARS-CoV-2 circulation and COVID-19 vaccination campaigns over the course of the pandemic affected immunity towards sHCoVs in the general population. To explore potential differences in immune recognition of sHCoVs in immunocompetent adults, we compared two cross-sectional cohorts: one sampled between 2018 and 2019 (pre-pandemic), the other at the end of the pandemic (February - March 2023). We compared serum IgG and IgA titers, antibody cross-reactivity patterns at the clonal level, and specificity towards Spike (S) domains for all sHCoVs and dominant SARS-CoV-2 variants by B-cell analysis. Subsequently, we determined the OC43 neutralization potential of sera and monoclonal antibodies targeting different S domains. In pre-pandemic individuals, SARS-CoV-2-reactive antibody and B-cell levels, and sHCoV/SARS-CoV-2 cross-reactivity were negligible. IgA and IgG reactivity against the S of sHCoVs was distributed over spike domain 1 and 2 (S1, S2). In end-pandemic donors, SARS-CoV-2-specific immune responses strongly dominated and the majority of sHCoV reactive clones cross-reacted with SARS-CoV-2. The SARS-CoV-2/sHCoVs cross-reactive clones accounted for higher NL63 S1- and OC43 S2-specific B-cell frequencies and matched higher serum antibody titers. For OC43, the immunodominance of SARS-CoV-2/OC43 cross-reactive IgG B-cells resulted in a strong bias towards S2. Serum OC43 neutralization titers were higher in end-pandemic donors and correlated with OC43 S1 and S2-specific IgG titers and reactive B-cells frequencies. However, the SARS-CoV-2/OC43 S2 cross-reactive IgG clones did not independently correlate with OC43 neutralization titers. We conclude that the establishment of SARS-CoV-2-specific immune responses altered responses to sHCoVs in our cohort, particularly for OC43 and NL63. This could have implications for the immune protection and offers insights for the development of pan-coronavirus treatments and vaccines.