Specific protein-protein interactions are essential for cellular functions. Experimentally determined three-dimensional structures of protein-protein complexes offer the possibility to characterize ...binding interfaces in terms of size, shape and packing density. Comparison with crystal-packing interfaces representing nonspecific protein-protein contacts gives insight into how specific binding differs from nonspecific low-affinity binding. An overview is given on empirical structural rules for specific protein-protein recognition derived from known complex structures. Although single parameters such as interface size, shape or surface complementary show clear trends for different interface types, each parameter alone is insufficient to fully distinguish between specific versus crystal-packing contacts. A combination of interface parameters is, however, well suited to characterize a specific interface. This knowledge provides us with the essential ingredients that make up a specific protein recognition site. It is also of great value for the prediction of protein binding sites and for the evaluation of predicted complex structures.
Very high-energy γ rays (VHE, E ≳ 100 GeV) propagating over cosmological distances can interact with the low-energy photons of the extragalactic background light (EBL) and produce electron-positron ...pairs. The transparency of the Universe to VHE γ rays is then directly related to the spectral energy distribution (SED) of the EBL. The observation of features in the VHE energy spectra of extragalactic sources allows the EBL to be measured, which otherwise is very difficult. An EBL model-independent measurement of the EBL SED with the H.E.S.S. array of Cherenkov telescopes is presented. It was obtained by extracting the EBL absorption signal from the reanalysis of high-quality spectra of blazars. From H.E.S.S. data alone the EBL signature is detected at a significance of 9.5σ, and the intensity of the EBL obtained in different spectral bands is presented together with the associated γ-ray horizon.
Pancreatic ductal adenocarcinoma (PDAC) is a deadly cancer that progresses without any symptom, and oftentimes, it is detected at an advanced stage. The lack of prior symptoms and effective ...treatments have created a knowledge gap in the management of this lethal disease. This issue can be addressed by developing novel noninvasive imaging-based biomarkers in PDAC. We explored in vivo hyperpolarized (HP) 13C MRS of pyruvate to lactate conversion and ex vivo 1H NMR spectroscopy in a panel of well-annotated patient-derived PDAC xenograft (PDXs) model and investigated the correlation between aberrant glycolytic metabolism and aggressiveness of the tumor. Real-time metabolic imaging data demonstrate the immediate intracellular conversion of HP 13C pyruvate to lactate after intravenous injection interrogating upregulated lactate dehydrogenase (LDH) activity in aggressive PDXs. Total ex vivo lactate measurement by 1H NMR spectroscopy showed a direct correlation with in vivo dynamic pyruvate-to-lactate conversion and demonstrated the potential of dynamic metabolic flux as a biomarker of total lactate concentration and aggressiveness of the tumor. Furthermore, the metabolite concentrations were very distinct among all four tumor types analyzed in this study. Overexpression of LDH-A and hypoxia-inducible factor (HIF-1α) plays a significant role in the conversion kinetics of HP pyruvate-to-lactate in tumors. Collectively, these data identified aberrant metabolic characteristics of pancreatic cancer PDXs and could potentially delineate metabolic targets for therapeutic intervention. Metabolic imaging with HP pyruvate and NMR metabolomics may enable identification and classification of aggressive subtypes of patient-derived xenografts. Translation of this real-time metabolic technique to the clinic may have the potential to improve the management of patients at high risk of developing pancreatic diseases.
Aims.
The identification of PeVatrons, hadronic particle accelerators reaching the knee of the cosmic ray spectrum (few × 10
15
eV), is crucial to understand the origin of cosmic rays in the ...Galaxy. We provide an update on the unidentified source HESS J1702-420, a promising PeVatron candidate.
Methods.
We present new observations of HESS J1702-420 made with the High Energy Stereoscopic System (H.E.S.S.), and processed using improved analysis techniques. The analysis configuration was optimized to enhance the collection area at the highest energies. We applied a three-dimensional likelihood analysis to model the source region and adjust non thermal radiative spectral models to the
γ
-ray data. We also analyzed archival
Fermi
Large Area Telescope data to constrain the source spectrum at
γ
-ray energies > 10 GeV.
Results.
We report the detection of
γ
-rays up to 100 TeV from a specific region of HESS J1702-420, which is well described by a new source component called HESS J1702-420A that was separated from the bulk of TeV emission at a 5.4
σ
confidence level. The power law
γ
-ray spectrum of HESS J1702-420A extends with an index of Γ = 1.53 ± 0.19
stat
± 0.20
sys
and without curvature up to the energy band 64−113 TeV, in which it was detected by H.E.S.S. at a 4.0
σ
confidence level. This makes HESS J1702-420A a compelling candidate site for the presence of extremely high energy cosmic rays. With a flux above 2 TeV of (2.08 ± 0.49
stat
± 0.62
sys
) × 10
−13
cm
−2
s
−1
and a radius of (0.06 ± 0.02
stat
± 0.03
sys
)°, HESS J1702-420A is outshone – below a few tens of TeV – by the companion HESS J1702-420B. The latter has a steep spectral index of Γ = 2.62 ± 0.10
stat
± 0.20
sys
and an elongated shape, and it accounts for most of the low-energy HESS J1702-420 flux. Simple hadronic and leptonic emission models can be well adjusted to the spectra of both components. Remarkably, in a hadronic scenario, the cut-off energy of the particle distribution powering HESS J1702-420A is found to be higher than 0.5 PeV at a 95% confidence level.
Conclusions.
For the first time, H.E.S.S. resolved two components with significantly different morphologies and spectral indices, both detected at > 5
σ
confidence level, whose combined emissions result in the source HESS J1702-420. We detected HESS J1702-420A at a 4.0
σ
confidence level in the energy band 64−113 TeV, which brings evidence for the source emission up to 100 TeV. In a hadronic emission scenario, the hard
γ
-ray spectrum of HESS J1702-420A implies that the source likely harbors PeV protons, thus becoming one of the most solid PeVatron candidates detected so far in H.E.S.S. data. However, a leptonic origin of the observed TeV emission cannot be ruled out either.
Peroxisome proliferator-activated receptor delta (PPARD) is a nuclear receptor known to play an essential role in regulation of cell metabolism, cell proliferation, inflammation, and tumorigenesis in ...normal and cancer cells. Recently, we found that a newly generated villin-PPARD mouse model, in which PPARD is overexpressed in villin-positive gastric progenitor cells, demonstrated spontaneous development of large, invasive gastric tumors as the mice aged. However, the role of PPARD in regulation of downstream metabolism in normal gastric and tumor cells is elusive. The aim of the present study was to find PPARD-regulated downstream metabolic changes and to determine the potential significance of those changes to gastric tumorigenesis in mice. Hyperpolarized 1-13C pyruvate magnetic resonance spectroscopy, nuclear magnetic resonance spectroscopy, and liquid chromatography-mass spectrometry were employed for metabolic profiling to determine the PPARD-regulated metabolite changes in PPARD mice at different ages during the development of gastric cancer, and the changes were compared to corresponding wild-type mice. Nuclear magnetic resonance spectroscopy-based metabolomic screening results showed higher levels of inosine monophosphate (p = 0.0054), uracil (p = 0.0205), phenylalanine (p = 0.017), glycine (p = 0.014), and isocitrate (p = 0.029) and lower levels of inosine (p = 0.0188) in 55-week-old PPARD mice than in 55-week-old wild-type mice. As the PPARD mice aged from 10 weeks to 35 weeks and 55 weeks, we observed significant changes in levels of the metabolites inosine monophosphate (p = 0.0054), adenosine monophosphate (p = 0.009), UDP-glucose (p = 0.0006), and oxypurinol (p = 0.039). Hyperpolarized 1-13C pyruvate magnetic resonance spectroscopy performed to measure lactate flux in live 10-week-old PPARD mice with no gastric tumors and 35-week-old PPARD mice with gastric tumors did not reveal a significant difference in the ratio of lactate to total pyruvate plus lactate, indicating that this PPARD-induced spontaneous gastric tumor development does not require glycolysis as the main source of fuel for tumorigenesis. Liquid chromatography-mass spectrometry-based measurement of fatty acid levels showed lower linoleic acid, palmitic acid, oleic acid, and steric acid levels in 55-week-old PPARD mice than in 10-week-old PPARD mice, supporting fatty acid oxidation as a bioenergy source for PPARD-expressing gastric tumors.
To be dormant or not depends on the origin and nature of both the cell and its niche. Similar to other cancer hallmarks, dormancy is ingrained with stemness, and stemness is embedded within dormancy. ...After all, cancer dormancy is dependent on multiple factors such as cell cycle arrest, metabolic inactivity, and the microenvironment. It is the net results and sum effects of a myriad of cellular interactions, interconnections, and interplays. When we unite all cancer networks and integrate all cancer hallmarks, we practice and preach a unified theory of cancer. From this perspective, we review cancer dormancy in the context of a stem cell theory of cancer. We revisit the seed and soil hypothesis of cancer. We reexamine its implications in both primary tumors and metastatic lesions. We reassess its roles in cell cycle arrest, metabolic inactivity, and stemness property. Cancer dormancy is particularly revealing when it informs us about the mysteries of late relapse, prolonged remission, and second malignancy. It is paradoxically rewarding when it delivers us the promises and power of cancer prevention and maintenance therapy in patient care.
In this study, 3D direct numerical simulations of a multi-component fuel consisting of CO,H2,H2O,CO2 and CH4 reacting with air are performed. A freely propagating turbulent premixed stoichiometric ...flame is simulated for both low and high turbulence conditions i.e., the rms values of turbulent velocity fluctuations normalised by the laminar flame speed are of order 1 and 10. A skeletal mechanism involving 49 reactions and 15 species, and a 5-step reduced mechanism with 9 species, are used in order to evaluate the performance of the reduced mechanism under turbulent conditions. The 5-step mechanism incurs significantly lower computational expenses compared to the skeletal mechanism. The majority of species mean mass fractions and mean reaction rates computed using these two mechanisms are in good agreement with one another. The mean progress variable and heat release rate variations across the flame brush are also recovered by the reduced mechanism. No major differences are observed in flame response to curvature or strain effects induced by turbulence, although some differences are observed in instantaneous flame structure. These differences are studied using a correlation coefficient and detailed analysis suggests that this comes from the fluctuating heat release induced effects in the case with higher turbulence level. Further considerations based on instantaneous reaction rate and local displacement speed are discussed to evaluate the suitability of the reduced mechanism.
We search for high-energy gamma-ray emission from the binary neutron star merger GW170817 with the H.E.S.S. Imaging Air Cherenkov Telescopes. The observations presented here have been obtained ...starting only 5.3 hr after GW170817. The H.E.S.S. target selection identified regions of high probability to find a counterpart of the gravitational-wave event. The first of these regions contained the counterpart SSS17a that has been identified in the optical range several hours after our observations. We can therefore present the first data obtained by a ground-based pointing instrument on this object. A subsequent monitoring campaign with the H.E.S.S. telescopes extended over several days, covering timescales from 0.22 to 5.2 days and energy ranges between to . No significant gamma-ray emission has been found. The derived upper limits on the very-high-energy gamma-ray flux for the first time constrain non-thermal, high-energy emission following the merger of a confirmed binary neutron star system.
•We observed a stellar occultation by Pluto on May 4, 2013.•The atmospheric pressure on Pluto at 1275 km was found to be 2.7 +/- 0.2 microbars from that event.•The only volatile transport models that ...are consistent with this new data have a high thermal inertia.•The high thermal inertia models have a global and collisional atmosphere throughout Pluto’s year.
Combining stellar occultation observations probing Pluto’s atmosphere from 1988 to 2013, and models of energy balance between Pluto’s surface and atmosphere, we find the preferred models are consistent with Pluto retaining a collisional atmosphere throughout its 248-year orbit. The occultation results show an increasing atmospheric pressure with time in the current epoch, a trend present only in models with a high thermal inertia and a permanent N2 ice cap at Pluto’s north rotational pole.
Aims. We report on the measurement and investigation of pulsed high-energy γ-ray emission from the Vela pulsar, PSR B0833−45, based on observations with the largest telescope of H.E.S.S., CT5, in ...monoscopic mode, and on data obtained with the Fermi-LAT. Methods. Data from 40.3 h of observations carried out with the H.E.S.S. II array from 2013 to 2015 have been used. A dedicated very low-threshold event reconstruction and analysis pipeline was developed to achieve the lowest possible energy threshold. Eight years of Fermi-LAT data were analysed and also used as reference to validate the CT5 telescope response model and analysis methods. Results. A pulsed γ-ray signal at a significance level of more than 15σ is detected from the P2 peak of the Vela pulsar light curve. Of a total of 15 835 events, more than 6000 lie at an energy below 20 GeV, implying a significant overlap between H.E.S.S. II-CT5 and the Fermi-LAT. While the investigation of the pulsar light curve with the LAT confirms characteristics previously known up to 20 GeV in the tens of GeV energy range, CT5 data show a change in the pulse morphology of P2, i.e. an extreme sharpening of its trailing edge, together with the possible onset of a new component at 3.4σ significance level. Assuming a power-law model for the P2 spectrum, an excellent agreement is found for the photon indices (Γ ≃ 4.1) obtained with the two telescopes above 10 GeV and an upper bound of 8% is derived on the relative offset between their energy scales. Using data from both instruments, it is shown however that the spectrum of P2 in the 10–100 GeV has a pronounced curvature; this is a confirmation of the sub-exponential cut-off form found at lower energies with the LAT. This is further supported by weak evidence of an emission above 100 GeV obtained with CT5. In contrast, converging indications are found from both CT5 and LAT data for the emergence of a hard component above 50 GeV in the leading wing (LW2) of P2, which possibly extends beyond 100 GeV. Conclusions. The detection demonstrates the performance and understanding of CT5 from 100 GeV down to the sub-20 GeV domain, i.e. unprecedented low energy for ground-based γ-ray astronomy. The extreme sharpening of the trailing edge of the P2 peak found in the H.E.S.S. II light curve of the Vela pulsar and the possible extension beyond 100 GeV of at least one of its features, LW2, provide further constraints to models of γ-Ray emission from pulsars.
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