Translation includes initiation, elongation, and termination, followed by ribosome recycling. We characterize a new sequence element in 5' untranslated regions that consists of an adjacent start and stop codon and thereby excludes elongation. In these start-stop elements, an initiating ribosome is simultaneously positioned for termination without having translocated. At the example of activating transcription factor 4 (ATF4), we demonstrate that start-stops modify downstream re-initiation, thereby repressing translation of upstream open reading frames and enhancing ATF4 inducibility under stress. Start-stop elements are abundant in both mammals and yeast and affect key regulators such as DROSHA and the oncogenic transcription factor NFIA. They provide a unique regulatory layer that impedes ribosome scanning without the energy-expensive peptide production that accompanies upstream open reading frames.

The serological response to the influenza virus vaccine is highly heterogeneous for reasons that are not entirely clear. While the impact of demographic factors such as age, body mass index (BMI), sex, prior vaccination and titer levels are known to impact seroconversion, they only explain a fraction of the response. To identify signatures of the vaccine response, we analyzed 273 protein levels from 138 serum samples of influenza vaccine recipients (2019–2020 season). We found that levels of proteins functioning in cholesterol transport were positively associated with seroconversion, likely linking to the known impact of BMI. When adjusting seroconversion for the demographic factors, we identified additional, unexpected signatures: proteins regulating actin cytoskeleton dynamics were significantly elevated in participants with high adjusted seroconversion. Viral strain specific analysis showed that this trend was largely driven by the H3N2 strain. Further, we identified complex associations between adjusted seroconversion and other factors: levels of proteins of the complement system associated positively with adjusted seroconversion in younger participants, while they were associated negatively in the older population. We observed the opposite trends for proteins of high density lipoprotein remodeling, transcription, and hemostasis. In sum, careful integrative modeling can extract new signatures of seroconversion from highly variable data that suggest links between the humoral response as well as immune cell communication and migration.

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The COVID-19 pandemic, triggered by severe acute respiratory syndrome coronavirus 2, has affected millions of people worldwide. Much research has been dedicated to our understanding of COVID-19 disease heterogeneity and severity, but less is known about recovery associated changes. To address this gap in knowledge, we quantified the proteome from serum samples from 29 recuperated COVID-19 patients and 29 age-, race-, and sex-matched healthy controls. Many proteins from pathways known to change upon acute COVID-19 illness, such as from the complement cascade, coagulation system, inflammation and adaptive immune system, had returned to levels seen in healthy controls. In comparison, we identified 22 and 15 proteins with significantly elevated and lowered levels, respectively, amongst recuperated COVID-19 cases compared to healthy controls. Some of the changes were similar to those observed for the acute phase of the disease, i.e. elevated levels of proteins from hemolysis, the adaptive immune systems, and inflammation. In contrast, some changes opposed those in the acute phase, e.g. elevated levels of CETP and APOA1 which function in lipid/cholesterol metabolism, and decreased levels of proteins from the complement cascade (e.g. C1R, C1, and VWF), the coagulation system (e.g. THBS1 and VWF), and the regulation of the actin cytoskeleton (e.g. PFN1 and CFL1) amongst recuperated COVID-19 cases. We speculate that some of these changes might originate from transient decreases in platelet counts upon recovery from the disease. Finally, we observed race-specific changes, e.g. with respect to immunoglobulins and cholesterol-metabolism-related proteins.