I-Motif Structures Formed in the Human c-MYC Promoter Are Highly Dynamic–Insights into Sequence Redundancy and I-Motif Stability

The GC-rich nuclease hypersensitivity element III1 (NHE III1) of the c-MYC promoter largely controls the transcriptional activity of the c-MYC oncogene. The C-rich strand in this region can form I-motif DNA secondary structures. We determined the folding pattern of the major I-motif formed in the NHE III1, which can be formed at near-neutral pH. While we find that the I-motif formed in the four 3′ consecutive runs of cytosines appears to be the most favored, our results demonstrate that the C-rich strand of the c-MYC NHE III1 exhibits a high degree of dynamic equilibration. Using a trisubstituted oligomer of this region, we determined the formation of two equilibrating loop isomers, one of which contains a flipped-out cytosine. Our results indicate that the intercalative cytosine+–cytosine base pairs are not always necessary for an intramolecular I-motif. The dynamic character of the c-MYC I-motif is intrinsic to the NHE III1 sequence and appears to provide stability to the c-MYC I-motif

Efficacious Intermittent Dosing of a Novel JAK2 Inhibitor in Mouse Models of Polycythemia Vera

A high percentage of patients with the myeloproliferative disorder polycythemia vera (PV) harbor a Val617→Phe activating mutation in the Janus kinase 2 (JAK2) gene, and both cell culture and mouse models have established a functional role for this mutation in the development of this disease. We describe the properties of MRLB-11055, a highly potent inhibitor of both the WT and V617F forms of JAK2, that has therapeutic efficacy in erythropoietin (EPO)-driven and JAK2V617F-driven mouse models of PV. In cultured cells, MRLB-11055 blocked proliferation and induced apoptosis in a manner consistent with JAK2 pathway inhibition. MRLB-11055 effectively prevented EPO-induced STAT5 activation in the peripheral blood of acutely dosed mice, and could prevent EPO-induced splenomegaly and erythrocytosis in chronically dosed mice. In a bone marrow reconstituted JAK2V617F-luciferase murine PV model, MRLB-11055 rapidly reduced the burden of JAK2V617F-expressing cells from both the spleen and the bone marrow. Using real-time in vivo imaging, we examined the kinetics of disease regression and resurgence, enabling the development of an intermittent dosing schedule that achieved significant reductions in both erythroid and myeloid populations with minimal impact on lymphoid cells. Our studies provide a rationale for the use of non-continuous treatment to provide optimal therapy for PV patients

Comparative physiology of Australian quolls (Dasyurus; Marsupialia)

Quolls (Dasyurus) are medium-sized carnivorous dasyurid marsupials. Tiger (3,840 g) and eastern quolls (780 g) are mesic zone species, northern quolls (516 g) are tropical zone, and chuditch (1,385 g) were once widespread through the Australian arid zone. We found that standard physiological variables of these quolls are consistent with allometric expectations for marsupials. Nevertheless, inter-specific patterns amongst the quolls are consistent with their different environments. The lower T ^sub b^ of northern quolls (34°C) may provide scope for adaptive hyperthermia in the tropics, and they use torpor for energy/water conservation, whereas the larger mesic species (eastern and tiger quolls) do not appear to. Thermolability varied from little in eastern (0.035°C °C^sup -1^) and tiger quolls (0.051°C ºC^sup -1^) to substantial in northern quolls (0.100°C ºC^sup -1^) and chuditch (0.146°C ºC^sup -1^), reflecting body mass and environment. Basal metabolic rate was higher for eastern quolls (0.662 ± 0.033 ml O^sub 2^ g^sup -1^ h^sup -1^), presumably reflecting their naturally cool environment. Respiratory ventilation closely matched metabolic demand, except at high ambient temperatures where quolls hyperventilated to facilitate evaporative heat loss; tiger and eastern quolls also salivated. A higher evaporative water loss for eastern quolls (1.43 ± 0.212 mg H^sub 2^O g^sup -1^ h^sup -1^) presumably reflects their more mesic distribution. The point of relative water economy was low for tiger (-1.3°C), eastern (-12.5°C) and northern (+3.3) quolls, and highest for the chuditch (+22.6°C). We suggest that these differences in water economy reflect lower expired air temperatures and hence lower respiratory evaporative water loss for the arid-zone chuditch relative to tropical and mesic quolls

Changes in asset operation management

W turbulentnym otoczeniu konieczne jest stałe dokonywanie zmian w systemie zarządzania przedsiębiorstwem w celu dostosowania metod zarządzania do tych zmian. Dotyczy to także zmian w metodach zarządzania eksploatacją środków trwałych. W oparciu o doświadczenia japońskie i amerykańskie ukształtowała się teoria obsługiwania od obsługiwania prewencyjnego do "najlepszych praktyk" w ramach koncepcji biznesowej strategii zarządzania eksploatacją.In turbulent environment it is necessary permanently to make changes in enterprise management system in order to adjust methods to the changes, what also causes changes in asset operation management. Based on Japanese and American experiences it was formed maintenance theory - from preventive maintenance to "best practices" - within the framework of business concept of operation management strategy