Distinguishing between Zika and dengue virus infections is critical for accurate treatment, but we still lack detailed understanding of their impact on their host. To identify new protein signatures of the two infections, we used next-generation proteomics to profile 122 serum samples from 62 Zika and dengue patients. We quantified >500 proteins and identified 13 proteins that were significantly differentially expressed (adjusted p-value < 0.05). These proteins typically function in infection and wound healing, with several also linked to pregnancy and brain function. We successfully validated expression differences with Carbonic Anhydrase 2 in both the original and an independent sample set. Three of the differentially expressed proteins, i.e., Fibrinogen Alpha, Platelet Factor 4 Variant 1, and Pro-Platelet Basic Protein, predicted Zika virus infection at a ∼70% true-positive and 6% false-positive rate. Further, we showed that intraindividual temporal changes in protein signatures can disambiguate diagnoses and serve as indicators for past infections. Taken together, we demonstrate that serum proteomics can provide new resources that serve to distinguish between different viral infections.

Colorectal cancer (CRC) is a heterogeneous disease that results from the accumulation of mutations in colonic mucosa cells. A subclass of CRC is characterized by microsatellite instability, which is thought to occur mainly through inactivation of the DNA mismatch repair genes MLH1 and MSH2. The inositol 5-phosphatase SHIP1 is expressed predominantly in hematopoietic cells. In this study, the expression of SHIP1 in carcinomas and its putative correlation with clinicopathologic parameters, expression of DNA repair genes and microsatellite instability was investigated. By analyzing a multi-tumor tissue microarray, expression of SHIP1 was detected in 48 out of 72 cancer entities analyzed. The expression of SHIP1 protein of 145 kDa was confirmed by Western blot analysis in 7 out of 14 carcinoma cell lines. Analysis of a large colorectal cancer tissue microarray with 1009 specimens revealed SHIP1 expression in 62% of the samples analyzed. SHIP1 expression was inversely correlated with lymph node metastasis, vascular invasion and tumor grade, and it was positively associated with left-sided tumor localization. Interestingly, a strong relationship between the expression of SHIP1 and nuclear and membranous beta-catenin and the DNA repair genes MLH1 and MSH2 was observed.

Zika virus (ZIKV) and dengue virus (DENV) are two closely related flaviviruses with similar symptoms. However, due to the implications of ZIKV infections for pregnancy outcomes, understanding differences in their molecular impact on the host is of high interest. Viral infections change the host proteome, including post-translational modifications. As modifications are diverse and of low abundance, they typically require additional sample processing which is not feasible for large cohort studies. Therefore, we tested the potential of next-generation proteomics data in its ability to prioritize specific modifications for later analysis. We re-mined published mass spectra from 122 serum samples from ZIKV and DENV patients for the presence of phosphorylated, methylated, oxidized, glycosylated/glycated, sulfated, and carboxylated peptides. We identified 246 modified peptides with significantly differential abundance in ZIKV and DENV patients. Amongst these, methionine-oxidized peptides from apolipoproteins and glycosylated peptides from immunoglobulin proteins were more abundant in ZIKV patient serum and generate hypotheses on the potential roles of the modification in the infection. The results demonstrate how data-independent acquisition techniques can help prioritize future analyses of peptide modifications.

Zusammenfassung: Hintergrund: Obduktionen gelten seit langem als der Goldstandard für die Qualitätssicherung in der Medizin. Die COVID-19-Pandemie hat ihr Potenzial für das Verständnis der Pathophysiologie, Therapie und Krankheitsbewältigung wieder in den Fokus gerückt. Im April 2020 wurde das Deutsche Register für COVID-19-Obduktionen (DeRegCOVID) eingerichtet, gefolgt vom Konsortium DEFEAT PANDEMIcs (2020–2021), das sich zum Nationalen Obduktionsnetzwerk (NATON) entwickelte. DeRegCOVID: DeRegCOVID sammelte und analysierte über 3 Jahre hinweg Obduktionsdaten von COVID-19-Verstorbenen in Deutschland und ist damit die größte nationale multizentrische Obduktionsstudie. Die Ergebnisse identifizierten entscheidende Faktoren für schwere/tödliche Fälle, wie z. B. pulmonale vaskuläre Thromboembolien, und das komplizierte Zusammenspiel von Virus und Immunsystem. DeRegCOVID diente als zentraler Hub für die Datenanalyse, Forschungsanfragen und öffentliche Kommunikation und spielte eine wichtige Rolle im Austausch mit Politik und öffentlichem Gesundheitswesen. NATON: NATON wurde vom Netzwerk Universitätsmedizin (NUM) initiiert und entwickelte sich zu einer nachhaltigen Infrastruktur für autopsiebasierte Forschung. Ziel ist die Bereitstellung einer Daten- und Methodenplattform, die die Zusammenarbeit zwischen Pathologie, Neuropathologie und Rechtsmedizin fördert. Die Struktur unterstützt eine rasche Rückkopplung zwischen Forschung, Patientenversorgung und Pandemiemanagement. Schlussfolgerung: DeRegCOVID hat wesentlich zum Verständnis der COVID-19-Pathophysiologie beigetragen. Durch seinen modularen Aufbau will das Nationale Obduktionsregister (NAREG) nun die Zusammenarbeit auf nationaler sowie internationaler Ebene weiter verbessern.

Studying tissue samples obtained during autopsies is the gold standard when diagnosing the cause of death and for understanding disease pathophysiology. Recently, the interest in post mortem minimally invasive biopsies has grown which is a less destructiveapproach in comparison to an open autopsy and reduces the risk of infection. While manual biopsies under ultrasound guidance are more widely performed, robotic post mortem biopsies have been recently proposed. This approach can further reduce the risk of infection for physicians. However, planning of the procedure and control of the robot need to be efficient and usable. We explore a virtual reality setup with a digital twin to realize fully remote planning and control of robotic post mortem biopsies. The setup is evaluated with forensic pathologists in a usability study for three interaction methods. Furthermore, we evaluate clinical feasibility and evaluate the system with three human cadavers. Overall, 132 needle insertions were performed with an off-axis needle placement error of 5.30 $\pm$ 3.25 mm. Tissue samples were successfully biopsied and histopathologically verified. Users reported a very intuitive needle placement approach, indicating that the system is a promising, precise, and low-risk alternative to conventional approaches.

Zika virus (ZIKV) and dengue virus (DENV) are two closely related flaviviruses with similar symptoms; understanding differences in their molecular impact on the host is therefore of high interest. Viruses interact with the host’s post-translational modifications, inducing changes visible in serum. As modifications are diverse and of low abundance, they typically require additional sample processing which is not feasible for large cohort studies. Therefore, we tested the potential of next-generation proteomics data in its ability to prioritize specific modifications for later targeted analysis. We re-mined published mass spectra from 122 unenriched serum samples from ZIKV and DENV patients for the presence of phosphorylated, methylated, oxidized, glycosylated/glycated, sulfated, and carboxylated peptides. We identified 272 modified peptides with significantly differential abundance in ZIKV and DENV patients. Amongst these, methionine-oxidized peptides from apolipoproteins and glycosylated peptides from immunoglobulin proteins were more abundant in ZIKV patient serum and generate hypotheses on the potential roles of the modification in the infection. The results demonstrate how data-independent acquisition techniques can help prioritize future analyses of peptide modifications.