No evidence for DNA N-6-methyladenine in mammals

N-6-methyladenine (6mdA) is a widespread DNA modification in bacteria. More recently, 6mdA has also been characterized in mammalian DNA. However, measurements of 6mdA abundance and profiles are often very dissimilar between studies, even when performed on DNA from identical mammalian cell types. Using comprehensive bioinformatics analyses of published data and novel experimental approaches, we reveal that efforts to assay 6mdA in mammals have been severely compromised by bacterial contamination, RNA contamination, technological limitations, and antibody nonspecificity. These complications render 6mdA an exceptionally problematic DNA modification to study and have resulted in erroneous detection of 6mdA in several mammalian systems. Together, our results strongly imply that the evidence published to date is not sufficient to support the presence of 6mdA in mammals.Funding Agencies|Swedish Research CouncilSwedish Research Council [2015-03495]; LiU-Cancer Network [2016-007]; Swedish Cancer SocietySwedish Cancer Society [CAN 2017/625]</p

Contribution to the epidemiological profile of main honey bee brood fungal diseases

The aim of this study was to determine the etiopathology and epidemiology of the honey bee brood diseases in Portugal. Honey bee brood samples were collected and analysed at the Laboratory of Honey Bee Pathology (LPAESAB) and Microbiology of IPB. Samples were processed for epidemiological characterization of fungal diseases of honey bee brood. In general, the prevalence of this fungal disease occurs along all the distritos and seasons of the country. The diagnosis of chalkbrood were higher (P<0,05) during summer than in the winter. The chalkbrood is the major fungal diseases of the honey bee brood presenting the higher concerns at regional and national level. Ascosphaera apis has been isolated from dry mummies analyzed by cultural methods, validating the diagnostic methodology previously used. Besides Aspergillus flavus and Aspergillus fumigatus has been isolated too from dry mummies, but there is still much that remains to be discovered in order to understanding chalkbrood and stonebrood epidemiology and etiopathology that will lead to improve management strategies of these diseases

A T cell receptor targeting a recurrent driver mutation in FLT3 mediates elimination of primary human acute myeloid leukemia in vivo

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Prevalent and immunodominant CD8 T cell epitopes are conserved in SARS-CoV-2 variants

Summary: The emergence of SARS-CoV-2 variants of concern (VOC) is driven by mutations that mediate escape from neutralizing antibodies. There is also evidence that mutations can cause loss of T cell epitopes. However, studies on viral escape from T cell immunity have been hampered by uncertain estimates of epitope prevalence. Here, we map and quantify CD8 T cell responses to SARS-CoV-2-specific minimal epitopes in blood drawn from April to June 2020 from 83 COVID-19 convalescents. Among 37 HLA ligands eluted from five prevalent alleles and an additional 86 predicted binders, we identify 29 epitopes with an immunoprevalence ranging from 3% to 100% among individuals expressing the relevant HLA allele. Mutations in VOC are reported in 10.3% of the epitopes, while 20.6% of the non-immunogenic peptides are mutated in VOC. The nine most prevalent epitopes are conserved in VOC. Thus, comprehensive mapping of epitope prevalence does not provide evidence that mutations in VOC are driven by escape of T cell immunity

A T cell receptor targeting a recurrent driver mutation in FLT3 mediates elimination of primary human acute myeloid leukemia in vivo

Acute myeloid leukemia (AML), the most frequent leukemia in adults, is driven by recurrent somatically acquired genetic lesions in a restricted number of genes. Treatment with tyrosine kinase inhibitors has demonstrated that targeting of prevalent FMS-related receptor tyrosine kinase 3 (FLT3) gain-of-function mutations can provide significant survival benefits for patients, although the efficacy of FLT3 inhibitors in eliminating FLT3-mutated clones is variable. We identified a T cell receptor (TCR) reactive to the recurrent D835Y driver mutation in the FLT3 tyrosine kinase domain (TCRFLT3D/Y). TCRFLT3D/Y-redirected T cells selectively eliminated primary human AML cells harboring the FLT3D835Y mutation in vitro and in vivo. TCRFLT3D/Y cells rejected both CD34+ and CD34− AML in mice engrafted with primary leukemia from patients, reaching minimal residual disease-negative levels, and eliminated primary CD34+ AML leukemia-propagating cells in vivo. Thus, T cells targeting a single shared mutation can provide efficient immunotherapy toward selective elimination of clonally involved primary AML cells in vivo.</p