Liver kinase B1 (LKB1) is mutationally inactivated in Peutz-Jeghers syndrome and in a variety of cancers including human papillomavirus (HPV)-caused cervical cancer. However, the significance of LKB1 ...mutations in cervical cancer initiation and progress has not been examined. Herein, we demonstrated that, in mouse embryonic fibroblasts, loss of LKB1 and transduction of HPV16 E6/E7 had an additive effect on constraining cell senescence while promoting cell proliferation and increasing glucose consumption, lactate production and ATP generation. Knockdown of LKB1 increased and ectopic expression of LKB1 decreased glycolysis, anchorage-independent cell growth, and cell migration and invasion in HPV-transformed cells. In the tumorigenesis and lung metastasis model in syngeneic mice, depletion of LKB1 markedly increased tumor metastatic colonies in lungs without affecting subcutaneous tumor growth. We showed that HPV16 E6/E7 enhanced the expression of hexokinase-ll (HK-II) in the glycolytic pathway through elevated c-MYC. Ectopic LKB1 reduced HK-II along with glycolysis. The inverse relationship between HK-II and LKB1 was also observed in normal and HPV-associated cervical lesions. We propose that LKB1 acts as a safeguard against HPV-stimulated aerobic glycolysis and tumor progression. These findings may eventually aid in the development of therapeutic strategy for HPV-associated malignancies by targeting cell metabolism.
A study was conducted to estimate the optimum requirement of dietary phosphorus (P) for Channa argus × Channa maculata. Effects of dietary P levels on the tissue composition, serum biochemical ...parameters and antioxidant status were also examined. Five practical diets were formulated to contain graded levels (4.8 g kg−1, 6.4 g kg−1, 7.9 g kg−1, 9.4 g kg−1 and 11.0 g kg−1) of available P from dietary ingredients and monocalcium phosphate (MCP). Each diet was randomly assigned to triplicate groups of 30 juvenile fish (initial body weight, 20.50 ± 0.53 g) for 8 weeks. The results showed that the specific growth rate (SGR) and weight gain (WG) were all significantly improved by dietary P up to 9.4 g kg−1 (P < 0.05) and then levelled off beyond this level. Broken‐line analysis showed maximum weight gain (WG) was obtained at dietary available P concentrations of 9.6 g kg−1. With the increase in dietary P level, protein efficiency rate (PER) increased significantly and reached a plateau, while the feed conversion ratio (FCR), the mesenteric lipid somatic index (MSI) and the whole‐body lipid content significantly reduced (P < 0.05). Dietary P levels also affected the mineralization (ash and P) of whole body, vertebrae and scale (P < 0.05). Quadratic analysis based on P contents in whole body, vertebrae, scale and ash content in vertebra indicated that the available P requirements were 10.4, 9.8, 10.0 and 10.3 g kg−1, respectively. However, no differences were found in the whole‐body moisture, crude protein, serum calcium (Ca) contents or Ca/P value, as well as the viscerosomatic index (VSI) and hepatosomatic index (HSI) among all the treatments (P > 0.05). Triglyceride (TG), total cholesterol (TC), high‐density lipoprotein cholesterol (HDL‐C) and low‐density lipoprotein cholesterol (LDL‐C) decreased significantly, while serum P content, HDL‐C/TC and HDL‐C/LDL‐C value increased significantly with dietary available P levels (P < 0.05). No significant changes in superoxide dismutase activity and malondialdehyde (MDA) content were observed (P > 0.05), but serum catalase (CAT) and glutathione peroxidase (GPx) activities and the ratio of CAT/SOD and GPx/SOD increased significantly with increasing dietary P levels (P < 0.05). In conclusion, the optimal P requirement of juvenile snakehead in practical feed was 9.6 g kg−1. Signs of P deficiency were characterized by poor growth, slightly reduced mineralization and the antioxidant capacity and an increase in body lipid content.
Abstract
HESS J1843–033 is a very high energy gamma-ray source whose origin remains unidentified. This work presents, for the first time, the energy spectrum of gamma rays beyond 100 TeV from the ...HESS J1843–033 region using the data recorded by the Tibet air shower array and its underground muon detector array. A gamma-ray source with an extension of 0.°34 ± 0.°12 is successfully detected above 25 TeV at (
α
,
δ
) = (281.°09 ± 0.°10, −3.°76 ± 0.°09) near HESS J1843–033 with a statistical significance of 6.2
σ
, and the source is named TASG J1844–038. The position of TASG J1844–038 is consistent with those of HESS J1843–033, eHWC J1842–035, and LHAASO J1843–0338. The measured gamma-ray energy spectrum in 25 TeV <
E
< 130 TeV is described with
dN
/
dE
=
(
9.70
±
1.89
)
×
10
−
16
(
E
/40 TeV)
−3.26±0.30
TeV
−1
cm
−2
s
−1
, and the spectral fit to the combined spectra of HESS J1843–033, LHAASO J1843–0338, and TASG J1844–038 implies the existence of a cutoff at 49.5 ± 9.0 TeV. Associations of TASG J1844–038 with SNR G28.6–0.1 and PSR J1844–0346 are also discussed in detail for the first time.
Abstract
Gamma rays from HESS J1849−000, a middle-aged TeV pulsar wind nebula (PWN), are observed by the Tibet air shower array and the muon detector array. The detection significance of gamma rays ...reaches 4.0
σ
and 4.4
σ
levels above 25 TeV and 100 TeV, respectively, in units of the Gaussian standard deviation
σ
. The energy spectrum measured between 40 TeV <
E
< 320 TeV for the first time is described with a simple power-law function of
dN
/
dE
=
(
2.86
±
1.44
)
×
10
−
16
(
E
/
40
TeV
)
−
2.24
±
0.41
TeV
−
1
cm
−
2
s
−
1
. The gamma-ray energy spectrum from the sub-TeV (
E
< 1 TeV) to sub-PeV (100 TeV <
E
< 1 PeV) ranges, including the results of previous studies, can be modeled with the leptonic scenario, i.e., inverse Compton scattering by high-energy electrons accelerated by the PWN of PSR J1849−0001. On the other hand, the gamma-ray energy spectrum can also be modeled with the hadronic scenario in which gamma rays are generated from the decay of neutral pions produced by collisions between accelerated cosmic-ray protons and the ambient molecular cloud found in the gamma-ray-emitting region. The cutoff energy of cosmic-ray protons
E
p,cut
is estimated as
log
10
(
E
p
,
cut
/
TeV
)
=
3.73
−
0.66
+
2.98
, suggesting that protons are accelerated up to the PeV energy range. Our study thus proposes that HESS J1849−000 should be further investigated as a new candidate as a Galactic PeV cosmic-ray accelerator, or “PeVatron.”
We present Van Allen Probe observation of drift‐resonance interaction between energetic electrons and ultralow frequency (ULF) waves on 29 October 2013. Oscillations in electron flux were observed at ...the period of ∼450 s, which is also the dominant period of the observed ULF magnetic pulsations. The phase shift of the electron fluxes (∼50 to 150 keV) across the estimated resonant energy (∼104 keV) is ∼360°. This phase relationship is different from the characteristic 180° phase shift as expected from the drift‐resonance theory. We speculate that the additional 180° phase difference arises from the inversion of electron phase space density (PSD) gradient, which in turn is caused by the drift motion of the substorm injected electrons. This PSD gradient adjusts the characteristic particle signatures in the drift‐resonance theory, which indicates a coupling effect between the magnetotail and the radiation belt and helps to better understand the wave‐particle interaction in the magnetosphere.
Key Points
Both electron flux oscillations in response to ULF waves and drift echoes of injected electrons are observed
A 360° phase shift in the electron fluxes modulated by ULF waves via drift‐resonance interaction is observed for the first time
The unusual phase relationship is associated with the inversion of PSD gradient caused by the drift motion of the injected electrons
Although electroacupuncture (EA) is effective in the relief of neuropathic pain, the underlying mechanisms remain unclear. Previous studies have reported immunomodulatory effects of EA in rats. Since ...excessive release of interferon-γ (IFN-γ) after nerve injury transforms quiescent spinal microglia into an activated state with more neuropathic pain, associated with purinergic receptor P2X4 expression, it is possible that EA may mediate its analgesic effect by attenuating IFN-γ release and subsequent generation of P2X4R+ microglia.
Male rats underwent chronic constriction injury (CCI) or IFN-γ intrathecal injection and von Frey tests were performed to evaluate the effect of EA on pain thresholds. Spinal IFN-γ and P2X4R expression levels were measured by immunohistochemistry, real-time PCR, enzyme immunoassay, and/or western blots. In vitro primary cultures of microglia were used to examine IFN-γ activation of P2X4R+ cells.
In CCI rats, EA treatment significantly increased paw withdrawal threshold relative to control. IFN-γ facilitated P2X4R+ microglia activation both in vitro and in vivo. EA also down-regulated both P2X4R and IFN-γ expression in the spinal cord after CCI. However, EA did not exert the same analgesic effect after intrathecal IFN-γ injection.
EA ameliorated tactile allodynia after peripheral nerve injury by down-regulating excessive expression of IFN-γ in the spinal cord and subsequently reducing expression of P2X4R.
Aims
The aim of this study was to determine the effects of unsaturated fatty acids on clinical plasmids.
Methods and Results
Two unsaturated fatty acids, linoleic acid (LA) and α‐linolenic acid (ALA) ...at final concentration 0, 0·03, 0·3 and 3 mmol l−1, respectively, were used to assess the effects on conjugative transfer of a mcr‐1‐harbouring plasmid pCSZ4 (IncX4) in conjugation experiment. The inhibitory mechanisms were analysed by molecular docking and the gene expression of virB11 was quantitated by qRT‐PCR. Target plasmid diversity was carried out by TrwD/VirB11 homology protein sequence prediction analysis. Our results showed that LA and ALA inhibit plasmid pCSZ4 transfer by binding to the amino acid residues (Phe124 and Thr125) of VirB11 with dose‐dependent effects. The expression levels of virB11 gene were also significantly inhibited by LA and ALA treatment. Protein homology analysis revealed a wide distribution of TrwD/VirB11‐like genes among over 37 classes of plasmids originated from both Gram‐negative and Gram‐positive bacteria.
Conclusions
This study demonstrates representing a diversity of plasmids that may be potentially inhibited by unsaturated fatty acids.
Significance and Impact of the Study
Our work reported here provides additional support for application of curbing the spread of multiple plasmids by unsaturated fatty acids.
We present an analysis of “boomerang‐shaped” pitch angle evolutions of outer radiation belt relativistic electrons observed by the Van Allen Probes after the passage of an interplanetary shock on 7 ...June 2014. The flux at different pitch angles is modulated by Pc5 waves, with equatorially mirroring electrons reaching the satellite first. For 90° pitch angle electrons, the phase change of the flux modulations across energy exceeds 180° and increasingly tilts with time. Using estimates of the arrival time of particles of different pitch angles at the spacecraft location, a scenario is investigated in which shock‐induced ULF waves interact with electrons through the drift resonance mechanism in a localized region westward of the spacecraft. Numerical calculations on particle energy gain with the modified ULF wavefield reproduce the observed boomerang stripes and modulations in the electron energy spectrogram. The study of boomerang stripes and their relationship to drift resonance taking place at a location different from the observation point adds new understanding of the processes controlling the dynamics of the outer radiation belt.
Key Points
Boomerang‐shaped pitch angle evolutions of relativistic electrons in Pc5 band is observed for the first time in the outer radiation belt
Electrons' drift resonating with azimuthally localized ULF waves can produce boomerang‐shaped pitch angle stripes
Nonlocal effects in drift‐resonant process on outer belt dynamics
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