Detection of Low Frequency Multi-Drug Resistance and Novel Putative Maribavir Resistance in Immunocompromised Pediatric Patients with Cytomegalovirus.

Human cytomegalovirus (HCMV) is a significant pathogen in immunocompromised individuals, with the potential to cause fatal pneumonitis and colitis, as well as increasing the risk of organ rejection in transplant patients. With the advent of new anti-HCMV drugs there is therefore considerable interest in using virus sequence data to monitor emerging resistance to antiviral drugs in HCMV viraemia and disease, including the identification of putative new mutations. We used target-enrichment to deep sequence HCMV DNA from 11 immunosuppressed pediatric patients receiving single or combination anti-HCMV treatment, serially sampled over 1-27 weeks. Changes in consensus sequence and resistance mutations were analyzed for three ORFs targeted by anti-HCMV drugs and the frequencies of drug resistance mutations monitored. Targeted-enriched sequencing of clinical material detected mutations occurring at frequencies of 2%. Seven patients showed no evidence of drug resistance mutations. Four patients developed drug resistance mutations a mean of 16 weeks after starting treatment. In two patients, multiple resistance mutations accumulated at frequencies of 20% or less, including putative maribavir and ganciclovir resistance mutations P522Q (UL54) and C480F (UL97). In one patient, resistance was detected 14 days earlier than by PCR. Phylogenetic analysis suggested recombination or superinfection in one patient. Deep sequencing of HCMV enriched from clinical samples excluded resistance in 7 of 11 subjects and identified resistance mutations earlier than conventional PCR-based resistance testing in 2 patients. Detection of multiple low level resistance mutations was associated with poor outcome

Capsule endoscopy in the investigation of patients with portal hypertension and anemia

INTRODUCTION: Data on small bowel abnormalities in patients with portal hypertension (PHT) are limited. Bleeding from the gastrointestinal tract and anemia are common complications in these patients. Capsule endoscopy (CE) was used to evaluate small bowel (SB) pathology in patients with PHT and anemia, and possible associations with various parameters were examined

HYPERION - A Decision Support System for Improved Resilience and Sustainable Reconstruction of historic areas

We introduce a research framework for downscaling the predicted/simulated climate and atmospheric conditions as well as associated risk maps down to the 1x1 km (historic area) scale, merging them with geohazard maps and integrating them with site and structure specific multi-hazard vulnerability functions to determine the time-varying risk for historical cities. Applying atmospheric modelling for specific Climate Change (CC) scenarios at such refined spatial and time scales allows for an accurate quantitative impact assessment of the estimated micro-climatic and atmospheric stressors. The ambition of this work, performed under the framework of the HYPERION EU-funded project, is to produce a comprehensive tool to assess the threats of CC in tandem with other natural hazards, visualize the built heritage and cultural landscape under future climate scenarios, model the effects of different adaptation strategies, and ultimately prioritize any rehabilitation actions to best allocate funds in both pre- and post-event environments

iTAG an optimized IMiD-induced degron for targeted protein degradation in human and murine cells

Summary: To address the limitation associated with degron based systems, we have developed iTAG, a synthetic tag based on IMiDs/CELMoDs mechanism of action that improves and addresses the limitations of both PROTAC and previous IMiDs/CeLMoDs based tags. Using structural and sequence analysis, we systematically explored native and chimeric degron containing domains (DCDs) and evaluated their ability to induce degradation. We identified the optimal chimeric iTAG(DCD23 60aa) that elicits robust degradation of targets across cell types and subcellular localizations without exhibiting the well documented “hook effect” of PROTAC-based systems. We showed that iTAG can also induce target degradation by murine CRBN and enabled the exploration of natural neo-substrates that can be degraded by murine CRBN. Hence, the iTAG system constitutes a versatile tool to degrade targets across the human and murine proteome