Asparagine, a critical limiting metabolite during glutamine starvation

A challenge of targeting glutamine metabolism in cancer is that tumor cells develop various strategies to adapt to glutamine limitation. We found that asparagine plays a critical role in supporting protein synthesis during glutamine starvation, highlighting a possible approach to optimize the therapeutic efficacy of targeting glutamine metabolism in cancer

As Extracellular Glutamine Levels Decline, Asparagine Becomes an Essential Amino Acid

When mammalian cells are deprived of glutamine, exogenous asparagine rescues cell survival and growth. Here we report that this rescue results from use of asparagine in protein synthesis. All mammalian cell lines tested lacked cytosolic asparaginase activity and could not utilize asparagine to produce other amino acids or biosynthetic intermediates. Instead, most glutamine-deprived cell lines are capable of sufficient glutamine synthesis to maintain essential amino acid uptake and production of glutamine-dependent biosynthetic precursors, with the exception of asparagine. While experimental introduction of cytosolic asparaginase could enhance the synthesis of glutamine and increase tricarboxylic acid cycle anaplerosis and the synthesis of nucleotide precursors, cytosolic asparaginase suppressed the growth and survival of cells in glutamine-depleted medium in vitro and severely compromised the in vivo growth of tumor xenografts. These results suggest that the lack of asparaginase activity represents an evolutionary adaptation to allow mammalian cells to survive pathophysiologic variations in extracellular glutamine

Promoter demethylation of the asparagine synthetase gene is required for ATF4-dependent adaptation to asparagine depletion

Tumor cells adapt to nutrient-limited environments by inducing gene expression that ensures adequate nutrients to sustain metabolic demands. For example, during amino acid limitations, ATF4 in the amino acid response induces expression of asparagine synthetase (ASNS), which provides for asparagine biosynthesis. Acute lymphoblastic leukemia (ALL) cells are sensitive to asparagine depletion, and administration of the asparagine depletion enzyme l-asparaginase is an important therapy option. ASNS expression can counterbalance l-asparaginase treatment by mitigating nutrient stress. Therefore, understanding the mechanisms regulating ASNS expression is important to define the adaptive processes underlying tumor progression and treatment. Here we show that DNA hypermethylation at the ASNS promoter prevents its transcriptional expression following asparagine depletion. Insufficient expression of ASNS leads to asparagine deficiency, which facilitates ATF4-independent induction of CCAAT-enhancer-binding protein homologous protein (CHOP), which triggers apoptosis. We conclude that chromatin accessibility is critical for ATF4 activity at the ASNS promoter, which can switch ALL cells from an ATF4-dependent adaptive response to ATF4-independent apoptosis during asparagine depletion. This work may also help explain why ALL cells are most sensitive to l-asparaginase treatment compared with other cancers

The origins and spread of domestic horses from the Western Eurasian steppes

This is the final version. Available on open access from Nature Research via the DOI in this recordData availability: All collapsed and paired-end sequence data for samples sequenced in this study are available in compressed fastq format through the European Nucleotide Archive under accession number PRJEB44430, together with rescaled and trimmed bam sequence alignments against both the nuclear and mitochondrial horse reference genomes. Previously published ancient data used in this study are available under accession numbers PRJEB7537, PRJEB10098, PRJEB10854, PRJEB22390 and PRJEB31613, and detailed in Supplementary Table 1. The genomes of ten modern horses, publicly available, were also accessed as indicated in their corresponding original publications57,61,85-87.NOTE: see the published version available via the DOI in this record for the full list of authorsDomestication of horses fundamentally transformed long-range mobility and warfare. However, modern domesticated breeds do not descend from the earliest domestic horse lineage associated with archaeological evidence of bridling, milking and corralling at Botai, Central Asia around 3500 BC. Other longstanding candidate regions for horse domestication, such as Iberia and Anatolia, have also recently been challenged. Thus, the genetic, geographic and temporal origins of modern domestic horses have remained unknown. Here we pinpoint the Western Eurasian steppes, especially the lower Volga-Don region, as the homeland of modern domestic horses. Furthermore, we map the population changes accompanying domestication from 273 ancient horse genomes. This reveals that modern domestic horses ultimately replaced almost all other local populations as they expanded rapidly across Eurasia from about 2000 BC, synchronously with equestrian material culture, including Sintashta spoke-wheeled chariots. We find that equestrianism involved strong selection for critical locomotor and behavioural adaptations at the GSDMC and ZFPM1 genes. Our results reject the commonly held association between horseback riding and the massive expansion of Yamnaya steppe pastoralists into Europe around 3000 BC driving the spread of Indo-European languages. This contrasts with the scenario in Asia where Indo-Iranian languages, chariots and horses spread together, following the early second millennium BC Sintashta culture

Intrachromosomal Rearrangements in Rodents from the Perspective of Comparative Region-Specific Painting

It has long been hypothesized that chromosomal rearrangements play a central role in different evolutionary processes, particularly in speciation and adaptation. Interchromosomal rearrangements have been extensively mapped using chromosome painting. However, intrachromosomal rearrangements have only been described using molecular cytogenetics in a limited number of mammals, including a few rodent species. This situation is unfortunate because intrachromosomal rearrangements are more abundant than interchromosomal rearrangements and probably contain essential phylogenomic information. Significant progress in the detection of intrachromosomal rearrangement is now possible, due to recent advances in molecular biology and bioinformatics. We investigated the level of intrachromosomal rearrangement in the Arvicolinae subfamily, a species-rich taxon characterized by very high rate of karyotype evolution. We made a set of region specific probes by microdissection for a single syntenic region represented by the p-arm of chromosome 1 of Alexandromys oeconomus, and hybridized the probes onto the chromosomes of four arvicolines (Microtus agrestis, Microtus arvalis, Myodes rutilus, and Dicrostonyx torquatus). These experiments allowed us to show the intrachromosomal rearrangements in the subfamily at a significantly higher level of resolution than previously described. We found a number of paracentric inversions in the karyotypes of M. agrestis and M. rutilus, as well as multiple inversions and a centromere shift in the karyotype of M. arvalis. We propose that during karyotype evolution, arvicolines underwent a significant number of complex intrachromosomal rearrangements that were not previously detected

Response of Transgenic Potato Plants Expressing Heterologous Genes of ∆9- or ∆12-Acyl-lipid Desaturases to <i>Phytophthora infestans</i> Infection

Late blight is one of the most economically important diseases affecting potato and causing a significant loss in yield. The development of transgenic potato plants with enhanced resistance to infection by Phytophthora infestans may represent a possible approach to solving this issue. A comparative study of the leaf response in control potato plants (S.tuberosum L. cultivar Skoroplodnyi), control transgenic plants expressing the reporter gene of thermostable lichenase (transgenic licBM3 line) and transgenic plants expressing cyanobacterial hybrid genes ∆9-acyl-lipid desaturase (transgenic desC lines) and ∆12-acyl-lipid desaturase (transgenic desA lines) to infection with P. infestans has been performed. The expression of desaturase genes in potato plants enhanced their tolerance to potato late blight agents as compared with the control. The lipid peroxidation level raised in the leaves of the control and transgenic desA plants on third day after inoculation with P. infestans zoospores and remained the same in the transgenic desC plants. The number of total phenolic compounds was increased as early as on the second day after infection in all studied variants and continued to remain the same, except for transgenic desC plants. Accumulation of flavonoids, the main components of the potato leaf phenolic complex, raised on the second day in all studied variants, remained unchanged on the third day in the control plants and decreased in most transgenic plants expressing desaturase genes. The results obtained in our study demonstrate that the expression of genes of Δ9- and Δ12-acyl-lipid desaturases in potato plants enhanced their resistance to P. infestans as compared with the control non-transgenic plants due to concomitant accumulation of phenolic compounds, including flavonoids, in the leaves. All these changes were more pronounced in transgenic desC plants, which indicates that the Δ9-acyllipid desaturase gene appears to be a potential inducer of the production of biological antioxidants in plant cells

Key indicators of obstetric and neonatal care in the Republic of Sakha (Yakutia)

In the absence of a medical birth registry, the official statistics are the only sources of information about pregnancy outcomes in the Republic of Sakha (Yakutia) (RS). We analysed the official statistical data about birth rate, fertility, infant and maternal mortality in the RS in the period 2003-2014. Compared with all- Russian data, the RS had a higher birth rate, especially in rural districts. Maternal and infant mortality were also higher compared with all-Russian data, but had a decreasing trend. The majority of deaths occurred in the small level 1 units. We suggest that establishment of good predelivery transportation of pregnant women with high risk of complications from remote areas and centralization of risk deliveries with improved prenatal and neonatal care could improve the pregnancy outcome in Yakutia