2,4-Disubstituted pyridine derivatives are effective against intracellular and biofilm-forming tubercle bacilli.

It was recently reported that 4-substituted picolinohydrazonamides carrying hydrophilic cyclic amines, such as morpholine and pyrrolidine, at the end of their thiosemicarbazide chain have potent antimycobacterial activity in vitro at concentrations below 1 µg/ml. Here, two selected compounds, 2,4-disubstituted pyridine derivatives 11 and 15, revealed significant bactericidal activity against Mycobacterium tuberculosis localized intracellularly within human macrophages, as well as against biofilm-forming tubercle bacilli. Mutants were selected that were resistant to the investigated compounds at an efficiency similar to that identified in the presence of the first line antituberculosis drug rifampicin. The resistant mutants were viable in the presence of the tested compounds exclusively on solid media. Genome-wide sequencing of the mutants selected in the presence of compound 11 revealed the accumulation of nonsynonymous mutations in the mmpR5 gene encoding a transcriptional repressor of the MmpS5-MmpL5 efflux pump, whose upregulation has been associated with bedaquiline resistance. The depletion of MmpR5 in wild-type M. tuberculosis using CRISPR-Cas9 technology increased the resistance of this strain to compound 11. Mass spectrometry-based proteomics (LC-MS/MS) of wild-type tubercle bacilli growing in subinhibitory concentrations of compounds 11 or 15 revealed 15 overproduced proteins not detectable in the control cells, including virulence-related proteins.

HRM screening of the UBC9 gene encoding the SUMO-E2-conjugating enzyme - case-control study in breast cancer.

AIM: UBC9 (E2) small ubiquitin-like modifier conjugating enzyme plays a key role in the post-translational modification of proteins named sumoylation. Defects in small ubiquitin-like modifier modification may contribute to breast carcinogenesis. In the present work, we examined UBC9 genetic variation. MATERIALS AND METHODS: UBC9 genetic variation was analyzed by using the high resolution melting (HRM) method. HRM study was conducted on 173-182 healthy women and 188-190 women with breast cancer. RESULTS: During HRM screening, we analysed three known single-nucleotide polymorphisms in introns: rs4984806, rs909916 and rs909917, and one known single nucleotide polymorphism rs8063 in exon 7, in a non-coding region. The genotype frequencies for all polymorphisms were in accordance with Hardy - Weinberg equilibrium among the control subjects and breast cancer patients. The linkage disequilibrium analysis displayed that there was one polymorphism block, which consisted of three single nucleotide polymorphisms: rs909916, rs909917 and rs4984806. We identified two common haplotypes CCG and TTC, but we did not find significant differences in the distribution of these haplotypes between cases and controls. CONCLUSION: Our study showed no differences in the occurrence of indicated polymorphisms in the UBC9 gene in a group of healthy women compared to women with breast cancer. These results suggest that the polymorphisms of the UBC9 gene - rs4984806, rs909916, rs909917 and rs8063 can be not associated with breast cancer risk.

BioSCOOP - Biobank Sample Communication Protocol. New approach for the transfer of information between biobanks.

Dynamic development of biobanking industry (both business and science) resulted in an increased number of IT systems for samples and data management. The most difficult and complicated case for the biobanking community was cooperation between institutions, equipped with different IT systems, in the field of scientific research, mainly data interchange and information flow. Tools available on the market relate mainly to the biobank or collection level. Efficient and universal protocols including the detailed information about the donor and the sample are still very limited. Here, we have developed BioSCOOP, a communication protocol in the form of a well documented JSON API. The main aim of this study was to harmonize and standardize the rules of communication between biobanks on the level of information about the donor together with information about the sample. The purpose was to create a communication protocol for two applications: to transfer the information between different biobanks and to allow the searching and presentation of the sample and data sets.

A genomic Neolithic time transect of hunter-farmer admixture in central Poland.

Ancient DNA genome-wide analyses of Neolithic individuals from central and southern Europe indicate an overall population turnover pattern in which migrating farmers from Anatolia and the Near East largely replaced autochthonous Mesolithic hunter-gatherers. However, the genetic history of the Neolithic transition in areas lying north of the European Neolithic core region involved different levels of admixture with hunter-gatherers. Here we analyse genome-wide data of 17 individuals spanning from the Middle Neolithic to the Early Bronze Age (4300-1900 BCE) in order to assess the Neolithic transition in north-central Poland, and the local impacts of hunter-farmer contacts and Late Neolithic steppe migrations. We evaluate the influence of these on local populations and assess if and how they change through time, reporting evidence of recurrent hunter-farmer admixture over three millennia, and the co-existence of unadmixed hunter-gatherers as late as 4300 BCE. During the Late Neolithic we report the appearance of steppe ancestry, but on a lesser scale than previously described for other central European regions, with evidence of stronger affinities to hunter-gatherers than to steppe pastoralists. These results help understand the Neolithic palaeogenomics of another central European area, Kuyavia, and highlight the complexity of population interactions during those times.

Association of five SNPs with human hair colour in the Polish population.

Twenty-two variants (single nucleotide polymorphisms - SNPs) of the genes involved in hair pigmentation (OCA2, HERC2, MC1R, SLC24A5, SLC45A2, TPCN2, TYR, TYRP1) were genotyped in a group of 186 Polish participants, representing a range of hair colours (45 red, 64 blond, 77 dark). A genotype-phenotype association analysis was performed. Using z-statistics we identified three variants highly associated with different hair colour categories (rs12913832:A>G in HERC2, rs1805007:T>C and rs1805008:C>T in MC1R). Two variants: rs1800401:C>T in OCA2 and rs16891982:C>G in SLC45A2 showed a high probability of a relation with hair colour, although that probability did not exceed the threshold of statistical significance after applying the Bonferroni correction. We created and validated mathematical logistic regression models in order to test the usefulness of the sets of polymorphisms for hair colour prediction in the Polish population. We subjected four models to stratified cross-validation. The first model consisted of three polymorphisms that proved to be important in the associative analysis. The second model included, apart from the mentioned polymorphisms, additionally rs16891982:C>G in SLC45A. The third model included, apart from the variants relevant in the associating analysis, rs1800401:C>T in OCA. The fourth model consisted of the set of polymorphisms from the first model supplemented with rs16891982:C>G in SLC45A and rs1800401:C>T in OCA. The validation of our models has shown that the inclusion of rs16891982:C>G in SLC45A and rs1800401:C>T in OCA increases the prediction of red hair in comparison with the algorithm including only rs12913832:A>G in HERC2, rs1805007:T>C and rs1805008:C>T in MC1R. The model consisting of all the five above-mentioned genetic variants has shown good prediction accuracies, expressed by the area under the curve (AUC) of the receiver operating characteristics: 0.84 for the red-haired, 0.82 for the dark-haired and 0.71 for the blond-haired. A genotype-phenotype association analysis brought results similar to those in other studies and confirmed the role of rs16891982:C>G, rs12913832:A>G, rs1805007:T>C and rs1805008:C>T in hair colour determination in the Polish population. Our study demonstrated for the first time the possibility of a share of the rs1800401:C>T SNP in the OCA2 gene in hair colour determination. Including this single nucleotide polymorphism in the actual hair colour predicting models would improve their predictive accuracy.