Genomic characterization of metastatic patterns from prospective clinical sequencing of 25,000 patients

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Using cryo-EM to understand antimycobacterial resistance in the catalase-peroxidase (KatG) from Mycobacterium tuberculosis

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Candidate Cancer Driver Mutations in Distal Regulatory Elements and Long-Range Chromatin Interaction Networks

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The spectrum of mutations and methods for their detection in the phenylalanine hydroxylase gene in phenylketonuria patients from the novosibirsk region

Phenylketonuria (PKU) is a widespread autosome recessive hereditary disease caused by a deficiency of the liver enzyme phenylalanine hydroxylase, which results in distortion of metabolism of phenylalanine and accumulation of toxic metabolites. The knowledge of molecular bases of PKU is of a high social importance as it enables phenotypic correction of the disease in the case of its early diagnostics. This disease is known to be associated with mutations in the phenylalanine hydroxylase gene, the distribution and mutation spectrum having pronounced ethnic and regional features. We studied the spectrum of mutations in the phenylalanine hydroxylase gene in a group of patients with PKU from the Novosibirsk region to reveal 10 missense point mutations, 1 mutation in the splice donor site, and 1 microdeletion. For these mutations, most widely distributed in the region, we used straightforward detection methods basing on the restriction fragment length polymorphism (RFLP), artificial constructed restriction sites (ACRS) PCR, and denaturing gradient gel electrophoresis (DGGE).     

Protamine amount and cross linking in mouse teratospermatozoa and aneuploid spermatozoa

The level of SH-group oxidation in spermatozoa from the cauda epididymis was measured by a cytofluorometric method in chromosomally normal mice and two chromosome mutants. The first one, a tertiary trisomic karyotype (Ts(1(13]7OH), is characterized by severe oligospermia and high levels (approximately 75%) of malformed spermatozoa. The second, a hybrid between two European feral mouse stocks, is heterozygous for multiple Robertsonian translocations and produces exclusively aneuploid spermatozoa. Neither the severe teratospermiogenesis nor the severe aneuploidy was reflected in total SH-group fluorescence values nor in free SH-group fluorescence. It is concluded that both the production of protamines and protamine cross linking by S-S bridge formation are rather autonomous processes during spermatogenesis because 1) the increased DNA variance of the aneuploid spermatozoa is not reflected in an increased variance of the total and free SH-groups, 2) aneuploidy for the protamine gene carrying chromosome 16 is not reflected by the SH-group values for individual spermatozoa, and 3) protamine production and cross linking are independent of the mild to severe terataspermiogenesis in the tertiary trisomic karyotype.     

Inference of Multisite Phosphorylation Rate Constants and Their Modulation by Pathogenic Mutations

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Watching Every Step of the Way: Junín Virus Attenuation Markers in the Vaccine Lineage

The Arenaviridae family includes several hemorrhagic fever viruses which are important emerging pathogens. Junín virus, a member of this family, is the etiological agent of Argentine Hemorrhagic Fever (AHF). A collaboration between the Governments of Argentina and the USA rendered the attenuated Junín virus vaccine strain Candid#1. Arenaviruses are enveloped viruses with genomes consisting of two single-stranded RNA species (L and S), each carrying two coding regions separated by a stably structured, non-coding intergenic region. Molecular characterization of the vaccine strain and of its more virulent ancestors, XJ13 (prototype) and XJ#44, allows a systematic approach for the discovery of key elements in virulence attenuation. We show comparisons of sequence information for the S RNA of the strains XJ13, XJ#44 and Candid#1 of Junín virus, along with other strains from the vaccine lineage and a set of Junín virus field strains collected at the AHF endemic area. Comparisons of nucleotide and amino acid sequences revealed different point mutations which might be linked to the attenuated phenotype. The majority of changes are consistent with a progressive attenuation of virulence between XJ13, XJ#44 and Candid#1. We propose that changes found in genomic regions with low natural variation frequencies are more likely to be associated with the virulence attenuation process. We partially sequenced field strains to analyze the genomic variability naturally occurring for Junín virus. This information, together with the sequence analysis of strains with intermediate virulence, will serve as a starting point to study the molecular bases for viral attenuation.