The Ras/Raf/mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway is often implicated in sensitivity and resistance to leukemia therapy. Dysregulated signaling ...through the Ras/Raf/MEK/ERK pathway is often the result of genetic alterations in critical components in this pathway as well as mutations at upstream growth factor receptors. Unrestricted leukemia proliferation and decreased sensitivity to apoptotic-inducing agents and chemoresistance are typically associated with activation of pro-survival pathways. Mutations in this pathway and upstream signaling molecules can alter sensitivity to small molecule inhibitors targeting components of this cascade as well as to inhibitors targeting other key pathways (for example, phosphatidylinositol 3 kinase (PI3K)/phosphatase and tensin homologue deleted on chromosome 10 (PTEN)/Akt/mammalian target of rapamycin (mTOR)) activated in leukemia. Similarly, PI3K mutations can result in resistance to inhibitors targeting the Ras/Raf/MEK/ERK pathway, indicating important interaction points between the pathways (cross-talk). Furthermore, the Ras/Raf/MEK/ERK pathway can be activated by chemotherapeutic drugs commonly used in leukemia therapy. This review discusses the mechanisms by which abnormal expression of the Ras/Raf/MEK/ERK pathway can contribute to drug resistance as well as resistance to targeted leukemia therapy. Controlling the expression of this pathway could improve leukemia therapy and ameliorate human health.
It has become apparent that regulation of protein translation is an important determinant in controlling cell growth and leukemic transformation. The phosphoinositide 3-kinase (PI3K)/phosphatase and ...tensin homologue deleted on chromosome ten (PTEN)/Akt/mammalian target of rapamycin (mTOR) pathway is often implicated in sensitivity and resistance to therapy. Dysregulated signaling through the PI3K/PTEN/Akt/mTOR pathway is often the result of genetic alterations in critical components in this pathway as well as mutations at upstream growth factor receptors. Furthermore, this pathway is activated by autocrine transformation mechanisms. PTEN is a critical tumor suppressor gene and its dysregulation results in the activation of Akt. PTEN is often mutated, silenced and is often haploinsufficient. The mTOR complex1 (mTORC1) regulates the assembly of the eukaryotic initiation factor4F complex, which is critical for the translation of mRNAs that are important for cell growth, prevention of apoptosis and transformation. These mRNAs have long 5'-untranslated regions that are G+C rich, rendering them difficult to translate. Elevated mTORC1 activity promotes the translation of these mRNAs via the phosphorylation of 4E-BP1. mTORC1 is a target of rapamycin and novel active-site inhibitors that directly target the TOR kinase activity. Although rapamycin and novel rapalogs are usually cytostatic and not cytotoxic for leukemic cells, novel inhibitors that target the kinase activities of PI3K and mTOR may prove more effective for leukemia therapy.
This paper describes properties and behavior of magnetic reconnection and flux transfer events (FTEs) on the dayside magnetopause using the global hybrid-Vlasov code Vlasiator. We investigate two ...simulation runs with and without a sunward (positive) B(sub x) component of the interplanetary magnetic field (IMF) when the IMF is southward. The runs are two-dimensional in real space in the noon-midnight meridional (polar) plane and three-dimensional in velocity space. Solar wind input parameters are identical in the two simulations with the exception that the IMF is purely southward in one but tilted 45° toward the Sun in the other. In the purely southward case (i.e., without B(sub x) the magnitude of the magnetosheath magnetic field component tangential to the magnetopause is larger than in the run with a sunward tilt. This is because the shock normal is perpendicular to the IMF at the equatorial plane, whereas in the other run the shock configuration is oblique and a smaller fraction of the total IMF strength is compressed at the shock crossing. Hence, the measured average and maximum reconnection rate are larger in the purely southward run. The run with tilted IMF also exhibits a north-south asymmetry in the tangential magnetic field caused by the different angle between the IMF and the bow shock normal north and south of the equator. Greater north-south asymmetries are seen in the FTE occurrence rate, size, and velocity as well; FTEs moving toward the Southern Hemisphere are larger in size and observed less frequently than FTEs in the Northern Hemisphere.
The potential of laser tweezers Raman spectroscopy (LTRS) to study complex and dynamic cellular processes was investigated on the model of single E. coli cells lysed (1) from "outside" with egg white ...lysozyme and (2) from "within" by temperature-induced temperate bacteriophage lambdacI857. The two lysis processes differed in the final outcome (incomplete vs complete cell lysis) as revealed by the dynamic laser light scattering and exhibited distinctive dynamic Raman spectra changes. The technique enabled for the first time at the cellular level to observe and quantify real time interaction of lysozyme with E. coli cells, "visualize" a side effect of the process due to the presence of EDTA, and correlate the process of cell wall disruption, as evidenced by the onset and development of asymmetric speckle scattering patterns, with release/escape of intracellular material (ribosomes, nucleic acids, proteins, etc.) quantified by the intensity changes of Raman signatures. Raman spectra changes observed during the lysis from "within" suggest alleged production of heat shock proteins are consistent with the occurring synthesis of phage-related proteins and are in good agreement with the calculated potential contribution of the above proteins to the Raman spectra. It was also established and validated that the contribution of cellular DNA to the Raman spectra of bacterial cells is negligible compared to RNA. The results open new venues for LTRS research and strongly suggest that LTRS has a great potential especially in investigation of real-time processes.
A potent, noncytotoxic indazole sulfonamide was identified by high-throughput screening of >100,000 synthetic compounds for activity against Mycobacterium tuberculosis (Mtb). This noncytotoxic ...compound did not directly inhibit cell wall biogenesis but triggered a slow lysis of Mtb cells as measured by release of intracellular green fluorescent protein (GFP). Isolation of resistant mutants followed by whole-genome sequencing showed an unusual gene amplification of a 40 gene region spanning from Rv3371 to Rv3411c and in one case a potential promoter mutation upstream of guaB2 (Rv3411c) encoding inosine monophosphate dehydrogenase (IMPDH). Subsequent biochemical validation confirmed direct inhibition of IMPDH by an uncompetitive mode of inhibition, and growth inhibition could be rescued by supplementation with guanine, a bypass mechanism for the IMPDH pathway. Beads containing immobilized indazole sulfonamides specifically interacted with IMPDH in cell lysates. X-ray crystallography of the IMPDH-IMP-inhibitor complex revealed that the primary interactions of these compounds with IMPDH were direct pi-pi interactions with the IMP substrate. Advanced lead compounds in this series with acceptable pharmacokinetic properties failed to show efficacy in acute or chronic murine models of tuberculosis (TB). Time-kill experiments in vitro suggest that sustained exposure to drug concentrations above the minimum inhibitory concentration (MIC) for 24 h were required for a cidal effect, levels that have been difficult to achieve in vivo. Direct measurement of guanine levels in resected lung tissue from tuberculosis-infected animals and patients revealed 0.5-2 mM concentrations in caseum and normal lung tissue. The high lesional levels of guanine and the slow lytic, growth-rate-dependent effect of IMPDH inhibition pose challenges to developing drugs against this target for use in treating TB.
Low-frequency radar sounders have the potential to generate altimetric profiles, but the feasibility of utilizing planetary radar sounding data as an alternative to laser altimetry has not been ...assessed using existing data to date. Therefore, we have developed, implemented, and evaluated an algorithm to process SHAllow RADar sounder (SHARAD) data on Mars (Experiment Data Records as available on the planetary data system) first into altimetry profiles and ultimately into digital terrain models (DTMs). The minimally processed data are pulse compressed, corrected for ionospheric distortion, zero-Doppler filtered, and incoherently summed. We then apply pulse re-tracking techniques adapted from terrestrial ocean altimetry to identify the surface return. From the surface return we compute the time-of-flight and hence the range from the spacecraft to the surface of the planet. The altimetry groundtracks are then co-registrated with Mars Orbiter Laser Altimeter (MOLA) to remove any biases resulting from residual ionospheric effects or timing issues. The altimetric profiles are finally used to create DTMs based on SHARAD data. While the SHARAD altimetry data have coarser inherent resolution than laser altimeters or imaging radars, we demonstrate that radar sounding data is still a viable source for satellite-based altimetry measurements. This is particularly important for future planetary missions not carrying laser altimeters but radar sounders, such as the upcoming Europa Clipper mission.
Recent studies have postulated that distinct regulatory cascades control myogenic differentiation in the head and the trunk. However, although the tissues and signaling molecules that induce skeletal ...myogenesis in the trunk have been identified, the source of the signals that trigger skeletal muscle formation in the head remain obscure. Here we show that although myogenesis in the trunk paraxial mesoderm is induced by Wnt signals from the dorsal neural tube, myogenesis in the cranial paraxial mesoderm is blocked by these same signals. In addition, BMP family members that are expressed in both the dorsal neural tube and surface ectoderm are also potent inhibitors of myogenesis in the cranial paraxial mesoderm. We provide evidence suggesting that skeletal myogenesis in the head is induced by the BMP inhibitors, Noggin and Gremlin, and the Wnt inhibitor, Frzb. These molecules are secreted by both cranial neural crest cells and by other tissues surrounding the cranial muscle anlagen. Our findings demonstrate that head muscle formation is locally repressed by Wnt and BMP signals and induced by antagonists of these signaling pathways secreted by adjacent tissues.
6 months after traumatic brain injury (TBI), almost three out of four patients suffer from sleep-wake disturbances (SWD) such as post-traumatic hypersomnia (increased sleep need of ≥2 h compared with ...before injury), excessive daytime sleepiness (EDS), fatigue and insomnia. The long-term course of post-traumatic SWD, however, is unknown.
To assess the prevalence and characteristics of post-traumatic SWD 3 years after trauma.
Prospective longitudinal clinical study in 51 consecutive TBI patients (43 males, eight females, mean age 40±16 years).
EDS (as assessed by the Epworth sleepiness scale), fatigue (fatigue severity scale), post-traumatic hypersomnia (sleep length per 24 h), insomnia, depression and anxiety.
Post-traumatic SWD were found in 34 patients (67%): post-traumatic hypersomnia in 14 (27%), EDS in six (12%), fatigue in 18 patients (35%) and insomnia in five patients (10%). SWD were not associated with severity or localisation of, or time interval since, TBI. Insomnia was linked to depressive symptoms.
This prospective study shows that 3 years after TBI, two out of three patients suffer from residual SWD, particularly fatigue and post-traumatic hypersomnia. In 45% of TBI patients, SWD appear directly related to the trauma itself.
Abstract
This paper describes properties and behavior of magnetic reconnection and flux transfer events (FTEs) on the dayside magnetopause using the global hybrid‐Vlasov code Vlasiator. We ...investigate two simulation runs with and without a sunward (positive)
B
x
component of the interplanetary magnetic field (IMF) when the IMF is southward. The runs are two‐dimensional in real space in the noon‐midnight meridional (polar) plane and three‐dimensional in velocity space. Solar wind input parameters are identical in the two simulations with the exception that the IMF is purely southward in one but tilted 45° toward the Sun in the other. In the purely southward case (i.e., without
B
x
) the magnitude of the magnetosheath magnetic field component tangential to the magnetopause is larger than in the run with a sunward tilt. This is because the shock normal is perpendicular to the IMF at the equatorial plane, whereas in the other run the shock configuration is oblique and a smaller fraction of the total IMF strength is compressed at the shock crossing. Hence, the measured average and maximum reconnection rate are larger in the purely southward run. The run with tilted IMF also exhibits a north‐south asymmetry in the tangential magnetic field caused by the different angle between the IMF and the bow shock normal north and south of the equator. Greater north‐south asymmetries are seen in the FTE occurrence rate, size, and velocity as well; FTEs moving toward the Southern Hemisphere are larger in size and observed less frequently than FTEs in the Northern Hemisphere.
Key Points
Sunward IMF tilt results in a smaller tangential field at the magnetopause, slowing dayside reconnection
Smaller tangential field results from a decrease in the IMF component that is shocked up at the bow shock
A positive IMF
B
x
component introduces north‐south asymmetries, where fewer (but larger) FTEs appear on the Southern Hemisphere
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