Serological assays can detect anti-SARS-CoV-2 (SARS2) antibodies, but their sensitivity often comes at the expense of specificity. Here we developed a Tripartite Automated Blood Immunoassay (TRABI) to assess the IgG response against SARS2. Calibration was per-formed with 90 prepandemic and 55 virologically and clinically confirmed COVID-19 sam-ples. Posterior probabilities of seropositivities were calculated from 3x8 measurements of logarithmically diluted samples against the ectodomain and the receptor-binding domain of the spike protein and the nucleoprotein. We then performed 760'320 assays on 5'503 prepandemic and 26'177 copandemic samples from hospital patients and healthy blood donors. We found 176 seropositive samples between December 2019 and May 2020. The seroprevalence increased conspicuously in March 2020 but plateaued in late April at 0.8-1.6% in both cohorts, indicating an equilibrium between new infections and the waning of immunity. This points to a high effectiveness of containment measures and/or to unex-pectedly rapid loss of humoral responses.

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Genome-wide CRISPR phenotypic screens are clarifying many fundamental biological phenomena. While pooled screens can be used to study selectable features, arrayed CRISPR libraries extend the screening territory to cell-nonautonomous, biochemical and morphological phenotypes. Using a novel high-fidelity liquid-phase plasmid cloning technology, we generated two human genome-wide arrayed libraries termed T.spiezzo (gene ablation, 19,936 plasmids) and T.gonfio (gene activation and epigenetic silencing, 22,442 plasmids). Each plasmid encodes four non-overlapping single-guide RNAs (sgRNAs), each driven by a unique housekeeping promoter, as well as lentiviral and transposable vector sequences. The sgRNAs were designed to tolerate most DNA polymorphisms identified in 10,000 human genomes, thereby maximizing their versatility. Sequencing confirmed that ~90% of each plasmid population contained ≥3 intact sgRNAs. Deletion, activation and epigenetic silencing experiments showed efficacy of 75-99%, up to 10,000x and 76-92%, respectively; lentiviral titers were ~10^7/ml. As a proof of concept, we investigated the effect of individual activation of each human transcription factor (n=1,634) on the expression of the cellular prion protein PrPC. We identified 24 upregulators and 12 downregulators of PrPC expression. Hence, the T.spiezzo and T.gonfio libraries represent a powerful resource for the individual perturbation of human protein-coding genes.

Many efforts targeting amyloid-β (Aβ) plaques for the treatment of Alzheimer's Disease thus far have resulted in failures during clinical trials. Regional and temporal heterogeneity of efficacy and dependence on plaque maturity may have contributed to these disappointing outcomes. In this study, we mapped the regional and temporal specificity of various anti-Aβ treatments through high-resolution light-sheet imaging of electrophoretically cleared brains. We assessed the effect on amyloid plaque formation and growth in Thy1-APP/PS1 mice subjected to β-secretase inhibitors, polythiophenes, or anti-Aβ antibodies. Each treatment showed unique spatiotemporal Aβ clearance, with polythiophenes emerging as a potent anti-Aβ compound. Furthermore, aligning with a spatial-transcriptomic atlas revealed transcripts that correlate with the efficacy of each Aβ therapy. As observed in this study, there is a striking dependence of specific treatments on the location and maturity of Aβ plaques. This may also contribute to the clinical trial failures of Aβ-therapies, suggesting that combinatorial regimens may be significantly more effective in clearing amyloid deposition.