Recurrent mutations in the U2AF1 splicing factor in myelodysplastic syndromes

Myelodysplastic syndromes (MDS) are hematopoietic stem cell disorders that often progress to chemotherapy-resistant secondary acute myeloid leukemia (sAML). We used whole-genome sequencing to perform an unbiased comprehensive screen to discover the somatic mutations in a sample from an individual with sAML and genotyped the loci containing these mutations in the matched MDS sample. Here we show that a missense mutation affecting the serine at codon 34 (Ser34) in U2AF1 was recurrently present in 13 out of 150 (8.7%) subjects with de novo MDS, and we found suggestive evidence of an increased risk of progression to sAML associated with this mutation. U2AF1 is a U2 auxiliary factor protein that recognizes the AG splice acceptor dinucleotide at the 3' end of introns, and the alterations in U2AF1 are located in highly conserved zinc fingers of this protein. Mutant U2AF1 promotes enhanced splicing and exon skipping in reporter assays in vitro. This previously unidentified, recurrent mutation in U2AF1 implicates altered pre-mRNA splicing as a potential mechanism for MDS pathogenesis

Para-infectious brain injury in COVID-19 persists at follow-up despite attenuated cytokine and autoantibody responses

To understand neurological complications of COVID-19 better both acutely and for recovery, we measured markers of brain injury, inflammatory mediators, and autoantibodies in 203 hospitalised participants; 111 with acute sera (1–11 days post-admission) and 92 convalescent sera (56 with COVID-19-associated neurological diagnoses). Here we show that compared to 60 uninfected controls, tTau, GFAP, NfL, and UCH-L1 are increased with COVID-19 infection at acute timepoints and NfL and GFAP are significantly higher in participants with neurological complications. Inflammatory mediators (IL-6, IL-12p40, HGF, M-CSF, CCL2, and IL-1RA) are associated with both altered consciousness and markers of brain injury. Autoantibodies are more common in COVID-19 than controls and some (including against MYL7, UCH-L1, and GRIN3B) are more frequent with altered consciousness. Additionally, convalescent participants with neurological complications show elevated GFAP and NfL, unrelated to attenuated systemic inflammatory mediators and to autoantibody responses. Overall, neurological complications of COVID-19 are associated with evidence of neuroglial injury in both acute and late disease and these correlate with dysregulated innate and adaptive immune responses acutely

Instrumentation and handling effects on Antarctic fur seals ( Arctocephalus gazella

The use of biologging instruments has greatly improved our understanding of the behaviour, physiology and ecology of free-ranging marine mammals. However, handling wild animals and attaching instruments to streamlined bodies can cause stress and potentially influence behaviour and swimming/diving energetics. The goals of this study, undertaken on Bouvetøya, were (1) to determine if the first trip to sea after instrumentation is representative of subsequent trips in lactating Antarctic fur seals, to explore potential handling effects and assess possible biases in having multiple short-duration deployments (inflating N, using a limited number of tags) and (2) to evaluate potential effects of two different instrument combinations (SMRU satellite data relay loggers and very high frequency radio transmitters versus Wildlife Computers time–depth recorders and very high frequency radio transmitters) on trip durations, dive parameters, female body condition and pup growth. Handling did not appear to have any effects on the parameters studied; data from the first and second trips did not differ significantly. This implies that multiple short-term deployments are unlikely to result in biased data in this species. Instrument type did have measurable effects; time-at-sea was greater and pup growth was lower for pairs in which mothers carried bulkier instruments. This suggests that instrument streamlining is important to avoid negative impacts and that bulkier equipment should be deployed on lactating females with caution and only for short periods. The study highlights that instrument effects should be taken into account when comparing data from experiments collected using different equipment packages