Origin and putative colonization routes for invasive rodent taxa in the democratic Republic of Congo

The threat posed by biological invasions is well established. An important consideration in preventing the spread of invasives and also subsequent introductions lies in understanding introduction pathways. The Democratic Republic of the Congo (DRC) houses a large percentage of the world's biodiversity, yet no national strategy exists to deal with the growing number of invasive alien species. Amongst these are the house mouse and ship and Norwegian rats. By comparing our result to published data, we show that species were possibly introduced into the DRC via two routes. The first is via the western seaport at Kinshasa where specimens of M. m. domesticus and R. rattus on the western and northwestern side of the DRC show ties with European haplotypes. The second is via the east where specimens of R. rattus appear linked to Arab and southeast Asian haplotypes. Future work should consider more comprehensive sampling throughout the DRC to more accurately investigate the occurrence of invasive species throughout the country as well as extend sampling to other African countries

Nucleic Acids Res

The HIV-1 dimerization initiation sequence (DIS) is a conserved palindrome in the apical loop of a conserved hairpin motif in the 5'-untranslated region of its RNA genome. DIS hairpin plays an important role in genome dimerization by forming a 'kissing complex' between two complementary hairpins. Understanding the kinetics of this interaction is key to exploiting DIS as a possible human immunodeficiency virus (HIV) drug target. Here, we present a single-molecule Förster resonance energy transfer (smFRET) study of the dimerization reaction kinetics. Our data show the real-time formation and dissociation dynamics of individual kissing complexes, as well as the formation of the mature extended duplex complex that is ultimately required for virion packaging. Interestingly, the single-molecule trajectories reveal the presence of a previously unobserved bent intermediate required for extended duplex formation. The universally conserved A272 is essential for the formation of this intermediate, which is stabilized by Mg2+, but not by K+ cations. We propose a 3D model of a possible bent intermediate and a minimal dimerization pathway consisting of three steps with two obligatory intermediates (kissing complex and bent intermediate) and driven by Mg2+ ions

Immunopeptidomics of colorectal cancer organoids reveals a sparse HLA class I neoantigen landscape and no increase in neoantigens with interferon or MEK-inhibitor treatment.

Patient derived organoids (PDOs) can be established from colorectal cancers (CRCs) as in vitro models to interrogate cancer biology and its clinical relevance. We applied mass spectrometry (MS) immunopeptidomics to investigate neoantigen presentation and whether this can be augmented through interferon gamma (IFNγ) or MEK-inhibitor treatment. Four microsatellite stable PDOs from chemotherapy refractory and one from a treatment naïve CRC were expanded to replicates with 100 million cells each, and HLA class I and class II peptide ligands were analyzed by MS. We identified an average of 9936 unique peptides per PDO which compares favorably against published immunopeptidomics studies, suggesting high sensitivity. Loss of heterozygosity of the HLA locus was associated with low peptide diversity in one PDO. Peptides from genes without detectable expression by RNA-sequencing were rarely identified by MS. Only 3 out of 612 non-silent mutations encoded for neoantigens that were detected by MS. In contrast, computational HLA binding prediction estimated that 304 mutations could generate neoantigens. One hundred ninety-six of these were located in expressed genes, still exceeding the number of MS-detected neoantigens 65-fold. Treatment of four PDOs with IFNγ upregulated HLA class I expression and qualitatively changed the immunopeptidome, with increased presentation of IFNγ-inducible genes. HLA class II presented peptides increased dramatically with IFNγ treatment. MEK-inhibitor treatment showed no consistent effect on HLA class I or II expression or the peptidome. Importantly, no additional HLA class I or II presented neoantigens became detectable with any treatment. Only 3 out of 612 non-silent mutations encoded for neoantigens that were detectable by MS. Although MS has sensitivity limits and biases, and likely underestimated the true neoantigen burden, this established a lower bound of the percentage of non-silent mutations that encode for presented neoantigens, which may be as low as 0.5%. This could be a reason for the poor responses of non-hypermutated CRCs to immune checkpoint inhibitors. MEK-inhibitors recently failed to improve checkpoint-inhibitor efficacy in CRC and the observed lack of HLA upregulation or improved peptide presentation may explain this

Flavour Issues in Leptogenesis

We study the impact of flavour in thermal leptogenesis, including the quantum oscillations of the asymmetries in lepton flavour space. In the Boltzmann equations we find different numerical factors and additional terms which can affect the results significantly. The upper bound on the CP asymmetry in a specific flavour is weaker than the bound on the sum. This suggests that -- when flavour dynamics is included -- there is no model-independent limit on the light neutrino mass scale,and that the lower bound on the reheat temperature is relaxed by a factor ~ (3 - 10).Comment: 19 pages, corrected equations for flavour oscillation

Evolutionary history and species delimitations: a case study of the hazel dormouse, Muscardinus avellanarius

Robust identification of species and significant evolutionary units (ESUs) is essential to implement appropriate conservation strategies for endangered species. However, definitions of species or ESUs are numerous and sometimes controversial, which might lead to biased conclusions, with serious consequences for the management of endangered species. The hazel dormouse, an arboreal rodent of conservation concern throughout Europe is an ideal model species to investigate the relevance of species identification for conservation purposes. This species is a member of the Gliridae family, which is protected in Europe and seriously threatened in the northern part of its range. We assessed the extent of genetic subdivision in the hazel dormouse by sequencing one mitochondrial gene (cytb) and two nuclear genes (BFIBR, APOB) and genotyping 10 autosomal microsatellites. These data were analysed using a combination of phylogenetic analyses and species delimitation methods. Multilocus analyses revealed the presence of two genetically distinct lineages (approximately 11 % cytb genetic divergence, no nuclear alleles shared) for the hazel dormouse in Europe, which presumably diverged during the Late Miocene. The phylogenetic patterns suggests that Muscardinus avellanarius populations could be split into two cryptic species respectively distributed in western and central-eastern Europe and Anatolia. However, the comparison of several species definitions and methods estimated the number of species between 1 and 10. Our results revealed the difficulty in choosing and applying an appropriate criterion and markers to identify species and highlight the fact that consensus guidelines are essential for species delimitation in the future. In addition, this study contributes to a better knowledge about the evolutionary history of the species

miR-15a-5p and miR-21-5p contribute to chemoresistance in cytogenetically normal acute myeloid leukaemia by targeting PDCD4, ARL2 and BTG2

Cytarabine and daunorubicin are old drugs commonly used in the treatment of acute myeloid leukaemia (AML). Refractory or relapsed disease because of chemotherapy resistance is a major issue. microRNAs (miRNAs) were incriminated in resistance. This study aimed to identify miRNAs involved in chemoresistance in AML patients and to define their target genes. We focused on cytogenetically normal AML patients with wild-type NPM1 without FLT3-ITD as the treatment of this subset of patients with intermediate-risk cytogenetics is not well established. We analysed baseline AML samples by small RNA sequencing and compared the profile of chemoresistant to chemosensitive AML patients. Among the miRNAs significantly overexpressed in chemoresistant patients, we revealed miR-15a-5p and miR-21-5p as miRNAs with a major role in chemoresistance in AML. We showed that miR-15a-5p and miR-21-5p overexpression decreased apoptosis induced by cytarabine and/or daunorubicin. PDCD4, ARL2 and BTG2 genes were found to be targeted by miR-15a-5p, as well as PDCD4 and BTG2 by miR-21-5p. Inhibition experiments of the three target genes reproduced the functional effect of both miRNAs on chemosensitivity. Our study demonstrates that miR-15a-5p and miR-21-5p are overexpressed in a subgroup of chemoresistant AML patients. Both miRNAs induce chemoresistance by targeting three pro-apoptotic genes PDCD4, ARL2 and BTG2

MartiTracks: A Geometrical Approach for Identifying Geographical Patterns of Distribution

Panbiogeography represents an evolutionary approach to biogeography, using rational cost-efficient methods to reduce initial complexity to locality data, and depict general distribution patterns. However, few quantitative, and automated panbiogeographic methods exist. In this study, we propose a new algorithm, within a quantitative, geometrical framework, to perform panbiogeographical analyses as an alternative to more traditional methods. The algorithm first calculates a minimum spanning tree, an individual track for each species in a panbiogeographic context. Then the spatial congruence among segments of the minimum spanning trees is calculated using five congruence parameters, producing a general distribution pattern. In addition, the algorithm removes the ambiguity, and subjectivity often present in a manual panbiogeographic analysis. Results from two empirical examples using 61 species of the genus Bomarea (2340 records), and 1031 genera of both plants and animals (100118 records) distributed across the Northern Andes, demonstrated that a geometrical approach to panbiogeography is a feasible quantitative method to determine general distribution patterns for taxa, reducing complexity, and the time needed for managing large data sets