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The parasite Trypanosoma brucei causes African sleeping sickness that is fatal to patients if untreated. Parasite differentiation from a replicative slender form into a quiescent stumpy form promotes host survival and parasite transmission. Long noncoding RNAs (lncRNAs) are known to regulate cell differentiation in other eukaryotes. To determine whether lncRNAs are also involved in parasite differentiation, we used RNA sequencing to survey the T. brucei genome, identifying 1428 previously uncharacterized lncRNA genes. We find that grumpy lncRNA is a key regulator that promotes parasite differentiation into the quiescent stumpy form. This function is promoted by a small nucleolar RNA encoded within the grumpy lncRNA. snoGRUMPY binds to messenger RNAs of at least two stumpy regulatory genes, promoting their expression. grumpy overexpression reduces parasitemia in infected mice. Our analyses suggest that T. brucei lncRNAs modulate parasite-host interactions and provide a mechanism by which grumpy regulates cell differentiation in trypanosomes.

Motivation: Log-rank test is a widely used test that serves to assess the statistical significance of observed differences in survival, when comparing two or more groups. The log-rank test is based on several assumptions that support the validity of the calculations. It is naturally assumed, implicitly, that no errors occur in the labeling of the samples. That is, the mapping between samples and groups is perfectly correct. In this work, we investigate how test results may be affected when considering some errors in the original labeling., Results: We introduce and define the uncertainty that arises from labeling errors in log-rank test. In order to deal with this uncertainty, we develop a novel algorithm for efficiently calculating a stability interval around the original log-rank P-value and prove its correctness. We demonstrate our algorithm on several datasets., Availability and Implementation: We provide a Python implementation, called LoRSI, for calculating the stability interval using our algorithm https://github.com/YakhiniGroup/LoRSI., Supplementary Information: Supplementary data are available at Bioinformatics online., (© The Author(s) 2021. Published by Oxford University Press.)

The parasite Trypanosoma brucei cycles between an insect and a mammalian host and is the causative agent of sleeping sickness. Here, we performed high-throughput mapping of pseudouridines (Ψs) on mRNA from two life stages of the parasite. The analysis revealed ~273 Ψs, including developmentally regulated Ψs that are guided by homologs of pseudouridine synthases (PUS1, 3, 5, and 7). Mutating the U that undergoes pseudouridylation in the 3' UTR of valyl-tRNA synthetase destabilized the mRNA level. To investigate the mechanism by which Ψ affects the stability of this mRNA, proteins that bind to the 3' UTR were identified, including the RNA binding protein RBSR1. The binding of RBSR1 protein to the 3' UTR was stronger when lacking Ψ compared to transcripts carrying the modification, suggesting that Ψ can inhibit the binding of proteins to their target and thus affect the stability of mRNAs. Consequently, Ψ modification on mRNA adds an additional level of regulation to the dominant post-transcriptional control in these parasites., (© 2021 John Wiley & Sons Ltd.)

Motivation and Background: The patient's immune system plays an important role in cancer pathogenesis, prognosis and susceptibility to treatment. Recent work introduced an immune related breast cancer. This subtyping is based on the expression profiles of the tumor samples. Specifically, one study showed that analyzing 658 genes can lead to a signature for subtyping tumors. Furthermore, this classification is independent of other known molecular and clinical breast cancer subtyping. Finally, that study shows that the suggested subtyping has significant prognostic implications., Results: In this work we develop an efficient signature associated with survival in breast cancer. We begin by developing a more efficient signature for the above-mentioned breast cancer immune-based subtyping. This signature represents better performance with a set of 579 genes that obtains an improved Area Under Curve (AUC). We then determine a set of 193 genes and an associated classification rule that yield subtypes with a much stronger statistically significant (log rank p-value < 2 × 10-4 in a test cohort) difference in survival. To obtain these improved results we develop a feature selection process that matches the high-dimensionality character of the data and the dual performance objectives, driven by survival and anchored by the literature subtyping., Competing Interests: The authors have declared that no competing interests exist.

The parasite Trypanosoma brucei is the causative agent of sleeping sickness and cycles between insect and mammalian hosts. The parasite appears to lack conventional transcriptional regulation of protein coding genes, and mRNAs are processed from polycistronic transcripts by the concerted action of trans- splicing and polyadenylation. Regulation of mRNA function is mediated mainly by RNA binding proteins affecting mRNA stability and translation. In this study, we describe the identification of 62 non-coding (nc) RNAs that are developmentally regulated and/or respond to stress. We characterized two novel anti-sense RNA regulators (TBsRNA-33 and 37) that originate from the rRNA loci, associate with ribosomes and polyribosomes, and interact in vivo with distinct mRNA species to regulate translation. Thus, this study suggests for the first-time anti-sense RNA regulators as an additional layer for controlling gene expression in these parasites., Competing Interests: The authors declare no competing financial interests., (© 2020 The Authors.)