In addition to glycolysis, the oncogenic transcription factor c-MYC (MYC) stimulates glutamine catabolism to fuel growth and proliferation of cancer cells through up-regulating glutaminase (GLS). ...Glutamine is converted to glutamate by GLS, entering the tricarboxylic acid cycle as an important energy source. Less wellrecognized, glutamate can also be converted to proline through ∆¹-pyrroline-5-carboxylate (P5C) and vice versa. This study suggests that some MYC-induced cellular effects are due to MYC regulation of proline metabolism. Proline oxidase, also known as proline dehydrogenase (POX/PRODH), the first enzyme in proline catabolism, is a mitochondrial tumor suppressor that inhibits proliferation and induces apoptosis. MiR-23b* mediates POX/PRODH down-regulation in human kidney tumors. MiR-23b* is processed from the same transcript as miR-23b; the latter inhibits the translation of GLS. Using MYC-inducible human Burkitt lymphoma model P493 and PC3 human prostate cancer cells, we showed that MYC suppressed POX/PRODH expression primarily through upregulating miR-23b*. The growth inhibition in the absence of MYC was partially reversed by POX/PRODH knockdown, indicating the importance of suppression of POX/PRODH in MYC-mediated cellular effects. Interestingly, MYC not only inhibited POX/PRODH, but also markedly increased the enzymes of proline biosynthesis from glutamine, including P5C synthase and P5C reductase 1. MYCinduced proline biosynthesis from glutamine was directly confirmed using ¹³ C, ¹⁵ N-glutamine as a tracer. The metabolic link between glutamine and proline afforded by MYC emphasizes the complexity of tumor metabolism. Further studies of the relationship between glutamine and proline metabolism should provide a deeper understanding of tumor metabolism while enabling the development of novel therapeutic strategies.
Because MYC plays a causal role in many human cancers, including those with hypoxic and nutrient-poor tumor microenvironments, we have determined the metabolic responses of a MYC-inducible human ...Burkitt lymphoma model P493 cell line to aerobic and hypoxic conditions, and to glucose deprivation, using stable isotope-resolved metabolomics. Using U-13C-glucose as the tracer, both glucose consumption and lactate production were increased by MYC expression and hypoxia. Using U-13C,15N-glutamine as the tracer, glutamine import and metabolism through the TCA cycle persisted under hypoxia, and glutamine contributed significantly to citrate carbons. Under glucose deprivation, glutamine-derived fumarate, malate, and citrate were significantly increased. Their 13C-labeling patterns demonstrate an alternative energy-generating glutaminolysis pathway involving a glucose-independent TCA cycle. The essential role of glutamine metabolism in cell survival and proliferation under hypoxia and glucose deficiency makes them susceptible to the glutaminase inhibitor BPTES and hence could be targeted for cancer therapy.
► P493 cells use glutamine for survival and proliferation in hypoxia ► P493 cells display a glucose-independent glutamine-driven TCA cycle ► Glutaminase inhibition diminishes in vitro and in vivo tumor cell growth
Abstract We report two phenomena detected in PSR J0344−0901 from two observations conducted at frequencies centered at 1.25 GHz using the Five-hundred-meter Aperture Spherical Radio Telescope. The ...first phenomenon manifests as the pulse emission shifting to later longitudinal phases and then gradually returning to its original location. The event lasts for about 216 pulse periods, with an average shift of about 0.°7 measured at the peak of the integrated profile. Changes in the polarization position angle (PPA) are detected around the trailing edge of the profile, together with an increase in the profile width. The second phenomenon is characterized by the apparent movement of subpulses, which results in different subpulse track patterns across the profile window. For the first time in this pulsar, we identify four emission modes, each with unique subpulse movement, and determine the pattern periods for three of them. Pulse nulling was not detected. Modeling of the changes in the PPA using the rotating vector model gives an inclination angle of 75.°12 ± 3.°80 and an impact parameter of −3.°17 ± 5.°32 for this pulsar. We speculate that the subpulse movement may be related to the shifting of the pulse emission.
Nucleotide synthesis is essential to proliferating cells, but the preferred precursors for de novo biosynthesis are not defined in human cancer tissues. We have employed multiplexed stable ...isotope-resolved metabolomics to track the metabolism of 13C6glucose, D2-glycine, 13C2glycine, and D3-serine into purine nucleotides in freshly resected cancerous and matched noncancerous lung tissues from nonsmall cell lung cancer (NSCLC) patients, and we compared the metabolism with established NSCLC PC9 and A549 cell lines in vitro. Surprisingly, 13C6glucose was the best carbon source for purine synthesis in human NSCLC tissues, in contrast to the noncancerous lung tissues from the same patient, which showed lower mitotic indices and MYC expression. We also observed that D3-Ser was preferentially incorporated into purine rings over D2-glycine in both tissues and cell lines. MYC suppression attenuated 13C6glucose, D3-serine, and 13C2glycine incorporation into purines and reduced proliferation in PC9 but not in A549 cells. Using detailed kinetic modeling, we showed that the preferred use of glucose as a carbon source for purine ring synthesis in NSCLC tissues involves cytoplasmic activation/compartmentation of the glucose–to–serine pathway and enhanced reversed one-carbon fluxes that attenuate exogenous serine incorporation into purines. Our findings also indicate that the substrate for de novo nucleotide synthesis differs profoundly between cancer cell lines and fresh human lung cancer tissues; the latter preferred glucose to exogenous serine or glycine but not the former. This distinction in substrate utilization in purine synthesis in human cancer tissues should be considered when targeting one-carbon metabolism for cancer therapy.
Abstract
We have carried out a detailed study of polarimetric individual pulse emission from the pulsar J1701−3726 (B1658−37), observed at 1369 MHz using the Parkes 64 m radio telescope. The ...single-pulse sequences reveal the presence of the three major emission phenomena of pulse nulling, mode changing, and subpulse drifting. Trimodal distribution of the pulse energy is present, implying one population of nulls and two others of emission in the phase window. The mean flux density of the normal mode is almost two times that of the abnormal mode. Our data show that, for PSR J1701−3726, 64% of the time was spent in the normal mode and 12% was in the abnormal mode. The single pulses show the presence of two distinct periodic modulations using a fluctuation spectral analysis. About 24% of the nulls are found to create alternating bunches of nulls and bursts in a quasiperiodic manner with a longer periodicity of 48 ± 4 rotational periods. Additionally, the pulsar presents a steady even–odd modulated feature with a stationary longitude within the pulse window. The ramifications for constraining the viewing geometry and understanding the radio emission mechanisms are discussed.
Abstract
We presented timing results of PSR B2035+36 using ∼9-yr observations with the Nanshan 25-m radio telescope. PSR B2035+36 was reported to exhibit significant changes in pulse profile ...correlated with spin-down state variations. We found that the pulsar underwent a glitch with a jump in frequency of $\Delta {\nu }\sim 12.4(5)\, \rm nHz$ around MJD 52950. Unusually, the spin-down rate increased persistently over 800 d after the glitch, and the average spin-down rate post-glitch was about $9.6 \, {per\,cent}$ larger than that pre-glitch. After the glitch activity, the pulse profile became narrower and the pulsar began to switch between two emission modes, with pulse widths ($W_{\ 50 \rm mean}$) of 8.5(7)° and 3.7(3)°, respectively. In addition to that, the relatively narrow pulse profile gradually became dominant. All of the observations indicate that there should be a connection between magnetospheric behaviour and glitch activity. We discuss one possibility of magnetosphere fluctuation triggered by the glitch event.
ABSTRACT
We report the phase-connected timing ephemeris, polarization pulse profiles, Faraday rotation measurements, and Rotating-Vector-Model (RVM) fitting results of 12 millisecond pulsars (MSPs) ...discovered with the Five-hundred-meter Aperture Spherical radio Telescope (FAST) in the Commensal Radio Astronomy FAST survey (CRAFTS). The timing campaigns were carried out with FAST and Arecibo over 3 yr. 11 of the 12 pulsars are in neutron star–white dwarf binary systems, with orbital periods between 2.4 and 100 d. 10 of them have spin periods, companion masses, and orbital eccentricities that are consistent with the theoretical expectations for MSP–Helium white dwarf (He WD) systems. The last binary pulsar (PSR J1912−0952) has a significantly smaller spin frequency and a smaller companion mass, the latter could be caused by a low orbital inclination for the system. Its orbital period of 29 d is well within the range of orbital periods where some MSP–He WD systems have shown anomalous eccentricities, however, the eccentricity of PSR J1912−0952 is typical of what one finds for the remaining MSP–He WD systems.
The Mode Switching in Pulsar J1326-6700 Wen, Z. G.; Yan, W. M.; Yuan, J. P. ...
Astrophysical journal/The Astrophysical journal,
11/2020, Volume:
904, Issue:
1
Journal Article
Peer reviewed
Open access
We report on a detailed study of the mode switching in pulsar J1326−6700 by analyzing the data acquired from the Parkes 64 m radio telescope at 1369 MHz. During the abnormal mode, the emission at the ...central and trailing components becomes extremely weak. Meanwhile, the leading emission shifts toward earlier longitude by almost 2°, and remains in this position for typically less than a minute. The mean flux density of the normal mode is almost five times that of the abnormal mode. Our data show that, for PSR J1326−6700, 85% of the time was spent in the normal mode and 15% was in the abnormal mode. The intrinsic distributions of mode timescales can be well described by Weibull distributions, which present a certain amount of memory in mode switching. Furthermore, a quasiperiodicity has been identified in the mode switching in pulsar J1326−6700. The estimated delay emission heights based on the kinematical effects indicate that the abnormal mode may have originated from higher altitude than the normal mode.
Abstract
PSR J2150+3427 is a 0.654 s pulsar discovered by the Commensal Radio Astronomy FAST Survey. From the follow-up observations, we find that the pulsar is in a highly eccentric orbit (
e
= ...0.601) with an orbital period of 10.592 days and a projected semimajor axis of 25.488 lt-s. Using 2.7 yr of timing data, we also measured the rate of periastron advance
ω
̇
= 0.0115(4) deg yr
−1
. An estimate for the total mass of the system using the
ω
̇
gives
M
tot
= 2.59(13)
M
⊙
, which is consistent with most of the known double neutron star (DNS) systems and one neutron star (NS)–white dwarf (WD) system named B2303+46. Combining
ω
̇
with the mass function of the system gives the masses of
M
p
< 1.67 and
M
c
> 0.98
M
⊙
for the pulsar and the companion star, respectively. This constraint, along with the spin period and orbital parameters, suggests that it is possibly a DNS system, and we cannot entirely rule out the possibility of an NS–WD system. Future timing observations will vastly improve the uncertainty in
ω
̇
, and are likely to allow the detection of additional relativistic effects, which can be used to modify the values of
M
p
and
M
c
. With a spin-down luminosity of
E
̇
= 5.07(6) × 10
29
erg s
−1
, PSR J2150+3427 is a very low-luminosity pulsar, with only the binary pulsar J2208+4610 having a smaller
E
̇
.
The mode of Fe uptake by the cyanobacterium Microcystis aeruginosa cultured in Fraquil* (pH 8) containing Suwannee River fulvic acid (SRFA) was examined using short-term radiolabeled 55Fe uptake ...assays and a kinetic model that describes extracellular Fe transformations. Both Fe(II) and Fe(III) uptake rates decreased substantially with increasing SRFA concentration as the availability of unchelated Fe decreased due to complexation by SRFA. Fe uptake rates under illuminated conditions were comparable to or slightly higher than those observed in the dark at the same Fe:SRFA concentration ratio, in contrast to results for systems containing ethylenediaminetetraacetic acid where Fe uptake rates were much greater under illumination than in the dark. The limited effect of light principally resulted from the relatively high rates of thermal dissociation and dark reduction of Fe(III) bound to SRFA and complexation of photogenerated Fe(II) by SRFA. Our findings imply that Fe uptake by M. aeruginosa at a fixed total Fe concentration of 200 nM is close to saturation when fulvic acid is present at concentrations near those typically found in natural waters (< ∼5 mg·L–1), with cellular growth likely to be limited by Fe availability only when natural organic matter is present at very high concentrations (>25 mg·L–1).
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